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Diodati NG, Qu G, Mehrad B, Schaller MA. Cryopreservation of human lung tissue for 3D ex vivo analysis. Respir Res 2025; 26:187. [PMID: 40375251 DOI: 10.1186/s12931-025-03265-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Accepted: 04/29/2025] [Indexed: 05/18/2025] Open
Abstract
Ex vivo culture techniques have assisted researchers in narrowing the translational gap between the lab and the clinic by allowing the study of biology in human tissues. In pulmonary biology, however, the availability of such tissues is a limiting factor in experimental design and constrains the reproducibility and replicability of these models as scientifically rigorous complements to in vitro or in vivo methods. Cryopreservation of human lung tissue is a strategy to address these limitations by generating cryopreserved biobanks of donors in the ex vivo study of pulmonary biology. Modern cryopreservation solutions, incorporating blends of cryoprotective extracellular macromolecules and cell-permeant non-toxic small molecules, have enabled the long-term storage of human lung tissue, allowing repeated experiments in the same donors and the simultaneous study of the same hypothesis across multiple donors, therefore granting the qualities of reproducibility and replicability to ex vivo systems. Specific considerations are required to properly maintain fundamental aspects of tissue structure, properties, and function throughout the cryopreservation process. The examples of existing cryopreservation systems successfully employed to amass cryobanks, and ex vivo culture techniques compatible with cryopreservation, are discussed herein, with the goal of indicating the potential of cryopreservation in ex vivo human lung tissue culture and highlighting opportunities for cryopreservation to expand the utility of ex vivo human lung culture systems in the pursuit of clinically relevant discoveries.
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Affiliation(s)
- Nickolas G Diodati
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA.
| | - Ganlin Qu
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA
| | - Borna Mehrad
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA
| | - Matthew A Schaller
- Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida College of Medicine, 1200 Newell Drive, Room MSB-M440, Gainesville, FL, 32610, USA
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Gordon JL, Boespflug EL, Coleman A, Taylor K, Cohen N, Yoon IK, Cassetti MC. Development of broadly protective coronavirus vaccines: A joint NIAID-CEPI workshop report. Vaccine 2025; 54:126909. [PMID: 40054139 DOI: 10.1016/j.vaccine.2025.126909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 02/10/2025] [Accepted: 02/17/2025] [Indexed: 05/13/2025]
Affiliation(s)
- Jennifer L Gordon
- National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). Bethesda, MD, USA..
| | | | - Amanda Coleman
- National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). Bethesda, MD, USA
| | - Kimberly Taylor
- National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). Bethesda, MD, USA
| | - Nadia Cohen
- Coalition for Epidemic Preparedness Innovations (CEPI). Oslo, Norway
| | - In-Kyu Yoon
- Coalition for Epidemic Preparedness Innovations (CEPI). Oslo, Norway
| | - M Cristina Cassetti
- National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). Bethesda, MD, USA
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Zhou J, Wei J, Wang H, Li H, Zhao L, Fu R, Yue B. Multiplex Detection of SNPs for Genetic Monitoring in Laboratory Mice by Luminex xTAG Assay. Genes (Basel) 2024; 15:1622. [PMID: 39766889 PMCID: PMC11675309 DOI: 10.3390/genes15121622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Background: The genetic quality of laboratory mice may have a direct impact on the results of research. Therefore, it is essential to improve genetic monitoring methods to guarantee research quality. However, few current methods boast high efficiency, high throughput, low cost, and general applicability at the same time. Methods: First, we got 34 SNP loci from previous studies for inbred strains and screened out 15 loci with good polymorphism for outbred groups from these 34 loci. Then, by using the Luminex xTAG assay, we tested inbred strains and outbred groups. Results: We tested commonly used inbred strains and five DNA samples from the International Council for Laboratory Animal Science, obtaining correct genotyping results. Additionally, some loci were potentially confirmed to be useful for distinguishing C57BL/6 and BALB/c mouse substrains. Furthermore, we tested three outbred groups and analyzed the genetic structure, and we compared the results of the SNP markers by xTAG assay to the STR markers by PCR, the trends of the three groups are the same. Conclusions: In our studies, the panels could meet the requirements for method promotion and provide a good choice for the genetic monitoring of inbred and outbred mice.
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Affiliation(s)
- Jiaqi Zhou
- Division of Laboratory Animal Monitoring, National Institutes for Food and Drug Control, Beijing 102629, China; (J.Z.); (J.W.); (H.W.); (H.L.)
- R&D Center, Beijing Minhai Biotechnology Co., Ltd., Beijing 102629, China
| | - Jie Wei
- Division of Laboratory Animal Monitoring, National Institutes for Food and Drug Control, Beijing 102629, China; (J.Z.); (J.W.); (H.W.); (H.L.)
| | - Hong Wang
- Division of Laboratory Animal Monitoring, National Institutes for Food and Drug Control, Beijing 102629, China; (J.Z.); (J.W.); (H.W.); (H.L.)
| | - Huan Li
- Division of Laboratory Animal Monitoring, National Institutes for Food and Drug Control, Beijing 102629, China; (J.Z.); (J.W.); (H.W.); (H.L.)
| | - Lan Zhao
- Division of Laboratory Animal Monitoring, National Institutes for Food and Drug Control, Beijing 102629, China; (J.Z.); (J.W.); (H.W.); (H.L.)
| | - Rui Fu
- Division of Laboratory Animal Monitoring, National Institutes for Food and Drug Control, Beijing 102629, China; (J.Z.); (J.W.); (H.W.); (H.L.)
| | - Bingfei Yue
- China National Rodent Laboratory Animal Resources Center, Beijing 102629, China
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Singh G, García-Bernalt Diego J, Warang P, Park SC, Chang LA, Noureddine M, Laghlali G, Bykov Y, Prellberg M, Yan V, Singh S, Pache L, Cuadrado-Castano S, Webb B, García-Sastre A, Schotsaert M. Outcome of SARS-CoV-2 reinfection depends on genetic background in female mice. Nat Commun 2024; 15:10178. [PMID: 39580470 PMCID: PMC11585546 DOI: 10.1038/s41467-024-54334-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 11/06/2024] [Indexed: 11/25/2024] Open
Abstract
Antigenically distinct SARS-CoV-2 variants increase the reinfection risk for vaccinated and previously exposed population due to antibody neutralization escape. COVID-19 severity depends on many variables, including host immune responses, which differ depending on genetic predisposition. To address this, we perform immune profiling of female mice with different genetic backgrounds -transgenic K18-hACE2 and wild-type 129S1- infected with the severe B.1.351, 30 days after exposure to the milder BA.1 or severe H1N1. Prior BA.1 infection protects against B.1.351-induced morbidity in K18-hACE2 but aggravates disease in 129S1. H1N1 protects against B.1.351-induced morbidity only in 129S1. Enhanced severity in B.1.351 re-infected 129S1 is characterized by an increase of IL-10, IL-1β, IL-18 and IFN-γ, while in K18-hACE2 the cytokine profile resembles naïve mice undergoing their first viral infection. Enhanced pathology during 129S1 reinfection cannot be attributed to weaker adaptive immune responses to BA.1. Infection with BA.1 causes long-term differential remodeling and transcriptional changes in the bronchioalveolar CD11c+ compartment. K18-hACE2 CD11c+ cells show a strong antiviral defense expression profile whereas 129S1 CD11c+ cells present a more pro-inflammatory response upon restimulation. In conclusion, BA.1 induces cross-reactive adaptive immune responses in K18-hACE2 and 129S1, but reinfection outcome correlates with differential CD11c+ cells responses in the alveolar space.
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Affiliation(s)
- Gagandeep Singh
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
| | - Juan García-Bernalt Diego
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
| | - Prajakta Warang
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
| | - Seok-Chan Park
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
| | - Lauren A Chang
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Moataz Noureddine
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gabriel Laghlali
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Department of Pharmaceutics, Ghent University, Ghent, Belgium
| | - Yonina Bykov
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matthew Prellberg
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Vivian Yan
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sarabjot Singh
- RT-PCR COVID-19 Laboratory, Civil Hospital, Moga, Punjab, India
| | - Lars Pache
- NCI Designated Cancer Center, Sanford-Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA
| | - Sara Cuadrado-Castano
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Lipschultz Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brett Webb
- Department of Veterinary Sciences, University of Wyoming, Laramie, WY, USA
| | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA
| | - Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA.
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai New York, New York, NY, USA.
- Lipschultz Precision Immunology Institute (PrIISM), Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Goens MM, Howard EL, Warner BM, Susta L, Wootton SK. Rapid Development of Small Rodent Animal Models for Infectious Disease Research Through Vectorized Receptor Molecule Expression. Viruses 2024; 16:1794. [PMID: 39599908 PMCID: PMC11599079 DOI: 10.3390/v16111794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/09/2024] [Accepted: 11/16/2024] [Indexed: 11/29/2024] Open
Abstract
The emergence and re-emergence of pathogens with pandemic potential has been a persistent issue throughout history. Recent decades have seen significant outbreaks of zoonotic viruses from members of the Coronaviridae, Filoviridae, Paramyxoviridae, Flaviviridae, and Togaviridae families, resulting in widespread infections. The continual emergence of zoonotic viral pathogens and associated infections highlights the need for prevention strategies and effective treatments. Central to this effort is the availability of suitable animal models, which are essential for understanding pathogenesis and assessing transmission dynamics. These animals are also critical for evaluating the safety and efficacy of novel vaccines or therapeutics and are essential in facilitating regulatory approval of new products. Rapid development of animal models is an integral aspect of pandemic response and preparedness; however, their establishment is fraught by several rate-limiting steps, including selection of a suitable species, the logistical challenges associated with sharing and disseminating transgenic animals (e.g., the time-intensive nature of breeding and maintaining colonies), the availability of technical expertise, as well as ethical and regulatory approvals. A method for the rapid development of relevant animal models that has recently gained traction, in large part due to the COVID-19 pandemic, is the use of gene therapy vectors to express human viral receptors in readily accessible laboratory animals to enable virus infection and development of clinical disease. These models can be developed rapidly on any genetic background, making mechanistic studies and accelerated evaluation of novel countermeasures possible. In this review, we will discuss important considerations for the effective development of animal models using viral vector approaches and review the current vector-based animal models for studying viral pathogenesis and evaluating prophylactic and therapeutic strategies, with an emphasis on models of SARS-CoV-2 infection based on the vectorized expression of human angiotensin-converting enzyme 2.
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Affiliation(s)
- Melanie M. Goens
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Erin L. Howard
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Bryce M. Warner
- Vaccine and Infectious Disease Organization, University of Saskatchewan, 120 Veterinary Rd, Saskatoon, SK S7N 5E3, Canada;
- Department of Biochemistry, Microbiology, and Immunology, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK S7N 5E5, Canada
| | - Leonardo Susta
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Sarah K. Wootton
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada
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6
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Shrwani KJ, Mahallawi WH, Mohana AI, Algaissi A, Dhayhi N, Sharwani NJ, Gadour E, Aldossari SM, Asiri H, Kameli N, Asiri AY, Asiri AM, Sherwani AJ, Cunliffe N, Zhang Q. Mucosal immunity in upper and lower respiratory tract to MERS-CoV. Front Immunol 2024; 15:1358885. [PMID: 39281686 PMCID: PMC11392799 DOI: 10.3389/fimmu.2024.1358885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 07/15/2024] [Indexed: 09/18/2024] Open
Abstract
INTRODUCTION Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged as a deadly pathogen with a mortality rate of up to 36.2%. MERS-CoV can cause severe respiratory tract disease and multiorgan failure. Therefore, therapeutic vaccines are urgently needed. This intensive review explores the human immune responses and their immunological mechanisms during MERS-CoV infection in the mucosa of the upper and lower respiratory tracts (URT and LRT, respectively). OBJECTIVE The aim of this study is to provide a valuable, informative, and critical summary of the protective immune mechanisms against MERS-CoV infection in the URT/LRT for the purpose of preventing and controlling MERS-CoV disease and designing effective therapeutic vaccines. METHODS In this review, we focus on the immune potential of the respiratory tract following MERS-CoV infection. We searched PubMed, Embase, Web of Science, Cochrane, Scopus, and Google Scholar using the following terms: "MERS-CoV", "B cells", "T cells", "cytokines", "chemokines", "cytotoxic", and "upper and lower respiratory tracts". RESULTS We found and included 152 studies in this review. We report that the cellular innate immune response, including macrophages, dendritic cells, and natural killer cells, produces antiviral substances such as interferons and interleukins to prevent the virus from spreading. In the adaptive and humoral immune responses, CD4+ helper T cells, CD8+ cytotoxic T cells, B cells, and plasma cells protect against MERS-CoV infection in URT and LRT. CONCLUSION The human nasopharynx-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT) could successfully limit the spread of several respiratory pathogens. However, in the case of MERS-CoV infection, limited research has been conducted in humans with regard to immunopathogenesis and mucosal immune responses due to the lack of relevant tissues. A better understanding of the immune mechanisms of the URT and LRT is vital for the design and development of effective MERS-CoV vaccines.
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Affiliation(s)
- Khalid J. Shrwani
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
- Public Health Authority, Saudi Center for Disease Prevention and Control (SCDC), Jazan, Saudi Arabia
| | - Waleed H. Mahallawi
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
| | - Abdulrhman I. Mohana
- Department of Antimicrobial Resistance, Public Health Authority, Riyadh, Saudi Arabia
| | - Abdullah Algaissi
- Department of Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
- Emerging and Endemic Infectious Diseases Research Unit, Health Sciences Research Center, Jazan University, Jazan, Saudi Arabia
| | - Nabil Dhayhi
- Department of Pediatrics, King Fahad Central Hospital, Ministry of Health, Gizan, Saudi Arabia
| | - Nouf J. Sharwani
- Department of Surgery, Mohammed bin Nasser Hospital, Ministry of Health, Gizan, Saudi Arabia
| | - Eyad Gadour
- Department of Gastroenterology and Hepatology, King Abdulaziz National Guard Hospital, Ahsa, Saudi Arabia
- Department of Medicine, Faculty of Medicine, Zamzam University College, Khartoum, Sudan
| | - Saeed M. Aldossari
- Medical Laboratory Technology Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Hasan Asiri
- Medical Laboratory Department, Prince Mohammed bin Abdulaziz Hospital, Riyadh, Saudi Arabia
| | - Nader Kameli
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Ayad Y. Asiri
- Intensive Care Unit Department, Al Inma Medical Group, Al Hayat National Hospital, Ministry of Health, Riyadh, Saudi Arabia
| | - Abdullah M. Asiri
- Preventive Medicine Assistant Deputyship, Ministry of Health, Riyadh, Saudi Arabia
| | - Alaa J. Sherwani
- Department of Pediatrics, Abu-Arish General Hospital, Ministry of Health, Gizan, Saudi Arabia
| | - Nigel Cunliffe
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Qibo Zhang
- Academic and Research Departments, Section of Immunology, School of Biosciences, University of Surrey, Surrey, United Kingdom
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Pechous RD, Malaviarachchi PA, Banerjee SK, Byrum SD, Alkam DH, Ghaffarieh A, Kurten RC, Kennedy JL, Zhang X. An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy. J Virol 2024; 98:e0079424. [PMID: 38940558 PMCID: PMC11265413 DOI: 10.1128/jvi.00794-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 06/10/2024] [Indexed: 06/29/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) has claimed millions of lives since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and lung disease appears the primary cause of death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors. Two cytokines in particular, IP-10 and IL-8, were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and thus ameliorated the histopathological changes caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs. IMPORTANCE Here, established an ex vivo human precision-cut lung slice platform for assessing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe coronavirus disease 2019 (COVID-19), and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.
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Affiliation(s)
- Roger D. Pechous
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Priyangi A. Malaviarachchi
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Srijon K. Banerjee
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Stephanie D. Byrum
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Arkansas Children’s Research Institute, Little Rock, Arkansas, USA
| | - Duah H. Alkam
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Alireza Ghaffarieh
- Department of Ophthalmology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Richard C. Kurten
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Lung Cell Biology Laboratory, Arkansas Children’s Research Institute, Little Rock, Arkansas, USA
| | - Joshua L. Kennedy
- Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
- Lung Cell Biology Laboratory, Arkansas Children’s Research Institute, Little Rock, Arkansas, USA
| | - Xuming Zhang
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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8
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Asplin P, Mancy R, Finnie T, Cumming F, Keeling MJ, Hill EM. Symptom propagation in respiratory pathogens of public health concern: a review of the evidence. J R Soc Interface 2024; 21:20240009. [PMID: 39045688 PMCID: PMC11267474 DOI: 10.1098/rsif.2024.0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 05/28/2024] [Indexed: 07/25/2024] Open
Abstract
Symptom propagation occurs when the symptom set an individual experiences is correlated with the symptom set of the individual who infected them. Symptom propagation may dramatically affect epidemiological outcomes, potentially causing clusters of severe disease. Conversely, it could result in chains of mild infection, generating widespread immunity with minimal cost to public health. Despite accumulating evidence that symptom propagation occurs for many respiratory pathogens, the underlying mechanisms are not well understood. Here, we conducted a scoping literature review for 14 respiratory pathogens to ascertain the extent of evidence for symptom propagation by two mechanisms: dose-severity relationships and route-severity relationships. We identify considerable heterogeneity between pathogens in the relative importance of the two mechanisms, highlighting the importance of pathogen-specific investigations. For almost all pathogens, including influenza and SARS-CoV-2, we found support for at least one of the two mechanisms. For some pathogens, including influenza, we found convincing evidence that both mechanisms contribute to symptom propagation. Furthermore, infectious disease models traditionally do not include symptom propagation. We summarize the present state of modelling advancements to address the methodological gap. We then investigate a simplified disease outbreak scenario, finding that under strong symptom propagation, isolating mildly infected individuals can have negative epidemiological implications.
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Affiliation(s)
- Phoebe Asplin
- EPSRC & MRC Centre for Doctoral Training in Mathematics for Real-World Systems, University of Warwick, Coventry, UK
- Mathematics Institute, University of Warwick, Coventry, UK
- The Zeeman Institute for Systems Biology & Infectious Disease Epidemiology Research, University of Warwick, Coventry, UK
| | - Rebecca Mancy
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Glasgow, UK
- MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Glasgow, UK
| | - Thomas Finnie
- Data, Analytics and Surveillance, UK Health Security Agency, London, UK
| | - Fergus Cumming
- Foreign, Commonwealth and Development Office, London, UK
| | - Matt J. Keeling
- Mathematics Institute, University of Warwick, Coventry, UK
- The Zeeman Institute for Systems Biology & Infectious Disease Epidemiology Research, University of Warwick, Coventry, UK
- School of Life Sciences, University of Glasgow, Glasgow, UK
| | - Edward M. Hill
- Mathematics Institute, University of Warwick, Coventry, UK
- The Zeeman Institute for Systems Biology & Infectious Disease Epidemiology Research, University of Warwick, Coventry, UK
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Chaudhury S, Kaur P, Gupta D, Anand P, Chaudhary M, Tiwari S, Mittal A, Gupta J, Kaur S, Singh VD, Dhawan D, Singh P, Sahu SK. Therapeutic Management with Repurposing Approaches: A Mystery During COVID-19 Outbreak. Curr Mol Med 2024; 24:712-733. [PMID: 37312440 DOI: 10.2174/1566524023666230613141746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 06/15/2023]
Abstract
The ubiquitous pandemic that emerged due to COVID-19 affected the whole planet. People all over the globe became vulnerable to the unpredictable emergence of coronavirus. The sudden emergence of respiratory disease in coronavirus infected several patients. This affected human life drastically, from mild symptoms to severe illness, leading to mortality. COVID-19 is an exceptionally communicable disease caused by SARS-CoV-2. According to a genomic study, the viral spike RBD interactions with the host ACE2 protein from several coronavirus strains and the interaction between RBD and ACE2 highlighted the potential change in affinity from the virus causing the COVID-19 outbreak to a progenitor type of SARS-CoV-2. SARS-CoV-2, which could be the principal reservoir, is phylogenetically related to the SARS-like bat virus. Other research works reported that intermediary hosts for the transmission of viruses to humans could include cats, bats, snakes, pigs, ferrets, orangutans, and monkeys. Even with the arrival of vaccines and individuals getting vaccinated and treated with FDAapproved repurposed drugs like Remdesivir, the first and foremost steps aimed towards the possible control and minimization of community transmission of the virus include social distancing, self-realization, and self-health care. In this review paper, we discussed and summarized various approaches and methodologies adopted and proposed by researchers all over the globe to help with the management of this zoonotic outbreak by following repurposed approaches.
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Affiliation(s)
- Soumik Chaudhury
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Paranjeet Kaur
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Deepali Gupta
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Palak Anand
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Manish Chaudhary
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Siddhita Tiwari
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Amit Mittal
- Faculty of Pharmaceutical Sciences, Desh Bhagat University, Amloh Road, Mandi Gobindgarh, 147301, Punjab, India
| | - Jeena Gupta
- School of Bioscience, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Sukhmeen Kaur
- Department of Opthalmology, Punjab Institute of Medical Sciences, Jalandhar, 144001, Punjab, India
| | - Varsh Deep Singh
- American University of Barbados, Wildey, St. Michael, BB11100, Barbados
| | - Dakshita Dhawan
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Princejyot Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
| | - Sanjeev Kumar Sahu
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, 144411, Punjab, India
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10
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Tuyskanova MS, Zhugunissov KD, Ozaslan M, Myrzakhmetova BS, Kutumbetov LB. [Clinical symptoms and signs in hamsters during experimental infection with the SARS-CoV-2 virus (Coronaviridae: Betacoronavirus)]. Vopr Virusol 2023; 68:513-525. [PMID: 38156567 DOI: 10.36233/0507-4088-202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Indexed: 12/30/2023]
Abstract
INTRODUCTION At the beginning of December 2019, humanity has faced a new problem caused by coronavirus. In Hubei province of central China, epidemic events associated with severe primary viral pneumonia in humans began to develop. The isolated etiological agent was identified as a representative of Coronaviridae family. The global pandemic associated with the new coronavirus infection, acute respiratory syndrome type 2 (Severe acute respiratory syndrome 2, SARS-CoV-2), has become a challenge for humanity. OBJECTIVE In our work, we assessed the replicative ability and pathogenesis of the SARS-CoV-2 virus in hamsters. MATERIALS AND METHODS Syrian hamsters (n=16) randomly divided into two groups were used in experiment. The first group was infected intranasally with the SARS-CoV-2 virus, strain SARS-CoV-2/human/KAZ/KZ_Almaty/2020 deposited in GenBank under number MZ379258.1. The second group remained as a control group. Clinical manifestations of the disease in hamsters were observed within 14 days. Samples were collected on days 3, 5, 7, 9, 12, and 14 postinfection. The obtained samples were tested for viral isolation in cell culture, histological examination and analysis of viral RNA by RT-PCR. RESULTS SARS-CoV-2 virus isolates showed efficient replication in the lungs of hamsters, causing pathological lung lesions in animals infected intranasally. Clinical manifestations of the disease in hamsters infected with this virus were characterized by a decrease in temperature and body weight, wetness and ruffled fur, and frequent stroking of the nasal planum. High virus titers were observed following the virus isolation in cell cultures from nasal, oral swabs and lungs of animals infected intranasally. Pathological autopsy demonstrated pathological changes in the lungs. Moreover, transmission by airborne droplets has been established when a healthy hamster was kept together with animals infected using the intranasal method. CONCLUSION In conclusion, our study showed that the Syrian hamster model is a useful tool for studying the SARS-CoV-2 pathogenesis, as well as testing vaccine candidates against acute respiratory syndrome type 2.
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Affiliation(s)
- M S Tuyskanova
- Research Institute for Biological Safety Problems
- Al-Farabi Kazakh National University
| | | | - M Ozaslan
- Department of Biology, Gaziantep University
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11
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Singh G, Warang P, García-Bernalt Diego J, Chang L, Bykov Y, Singh S, Pache L, Cuadrado-Castano S, Webb B, Garcia-Sastre A, Schotsaert M. Host immune responses associated with SARS-CoV-2 Omicron infection result in protection or pathology during reinfection depending on mouse genetic background. RESEARCH SQUARE 2023:rs.3.rs-3637405. [PMID: 38077015 PMCID: PMC10705603 DOI: 10.21203/rs.3.rs-3637405/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Rapid emergence of antigenic distinct SARS-CoV-2 variants implies a greater risk of reinfection as viruses can escape neutralizing antibodies induced by vaccination or previous viral exposure. Disease severity during COVID-19 depends on many variables such as age-related comorbidities, host immune status and genetic variation. The host immune response during infection with SARS-CoV-2 may contribute to disease severity, which can range from asymptomatic to severe with fatal outcome. Furthermore, the extent of host immune response activation may rely on underlying genetic predisposition for disease or protection. To address these questions, we performed immune profiling studies in mice with different genetic backgrounds - transgenic K18-hACE2 and wild-type 129S1 mice - subjected to reinfection with the severe disease-causing SARS-CoV-2 B.1.351 variant, 30 days after experimental milder BA.1 infection. BA.1 preinfection conferred protection against B.1.351-induced morbidity in K18-hACE2 mice but aggravated disease in 129S1 mice. We found that he cytokine/chemokine profile in B.1.351 re-infected 129S1mice is similar to that during severe SARS-CoV-2 infection in humans and is characterized by a much higher level of IL-10, IL-1β, IL-18 and IFN-γ, whereas in B.1.351 re-infected K18-hACE2 mice, the cytokine profile echoes the signature of naïve mice undergoing viral infection for the first time. Interestingly, the enhanced pathology observed in 129S1 mice upon reinfection cannot be attributed to a less efficient induction of adaptive immune responses to the initial BA.1 infection, as both K18-hACE2 and 129S1 mice exhibited similar B and T cell responses at 30 DPI against BA.1, with similar anti-BA.1 or B.1.351 spike-specific ELISA binding titers, levels of germinal center B-cells, and SARS-CoV-2-Spike specific tissue-resident T-cells. Long-term effects of BA.1 infection are associated with differential transcriptional changes in bronchoalveolar lavage-derived CD11c + immune cells from K18-hACE2 and 129S1, with K18-hACE2 CD11c + cells showing a strong antiviral defense gene expression profile whereas 129S1 CD11c + cells showed a more pro-inflammatory response. In conclusion, initial infection with BA.1 induces cross-reactive adaptive immune responses in both K18-hACE2 and 129S1 mice, however the different disease outcome of reinfection seems to be driven by differential responses of CD11c + cells in the alveolar space.
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Affiliation(s)
| | | | | | | | | | - Sarabjot Singh
- RT-PCR COVID-19 Laboratory, Civil Hospital, Moga, Punjab, India
| | - Lars Pache
- Sanford Burnham Prebys Medical Discovery Institute
| | | | - Brett Webb
- Department of Veterinary Sciences, University of Wyoming
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12
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Ma Y, Zhong J, Zhu N. Weighted hypergraph learning and adaptive inductive matrix completion for SARS-CoV-2 drug repositioning. Methods 2023; 219:102-110. [PMID: 37804962 DOI: 10.1016/j.ymeth.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 09/14/2023] [Accepted: 10/03/2023] [Indexed: 10/09/2023] Open
Abstract
MOTIVATION The outbreak of the human coronavirus (SARS-CoV-2) has placed a huge burden on public health and the world economy. Compared with de novo drug discovery, drug repurposing is a promising therapeutic strategy that facilitates rapid clinical treatment decisions, shortens the development process, and reduces costs. RESULTS In this study, we propose a weighted hypergraph learning and adaptive inductive matrix completion method, WHAIMC, for predicting potential virus-drug associations. Firstly, we integrate multi-source data to describe viruses and drugs from multiple perspectives, including drug chemical structures, drug targets, virus complete genome sequences, and virus-drug associations. Then, WHAIMC establishes an adaptive inductive matrix completion model to improve performance through adaptive learning of similarity relations. Finally, WHAIMC introduces weighted hypergraph learning into adaptive inductive matrix completion to capture higher-order relationships of viruses (or drugs). The results showed that WHAIMC had a strong predictive performance for new virus-drug associations, new viruses, and new drugs. The case study further demonstrates that WHAIMC is highly effective for repositioning antiviral drugs against SARS-CoV-2 and provides a new perspective for virus-drug association prediction. The code and data in this study is freely available at https://github.com/Mayingjun20179/WHAIMC.
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Affiliation(s)
- Yingjun Ma
- School of Mathematics and Statistics, Xiamen University of Technology, Xiamen 361024, China.
| | - Junjiang Zhong
- School of Mathematics and Statistics, Xiamen University of Technology, Xiamen 361024, China
| | - Nenghui Zhu
- School of Mathematics and Statistics, Xiamen University of Technology, Xiamen 361024, China
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13
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Lin HF, Liu MQ, Jiang RD, Gong QC, Su J, Guo ZS, Chen Y, Jia JK, Dong TY, Zhu Y, Li A, Shen XR, Wang Y, Li B, Xie TT, Yang XL, Hu B, Shi ZL. Characterization of a mouse-adapted strain of bat severe acute respiratory syndrome-related coronavirus. J Virol 2023; 97:e0079023. [PMID: 37607058 PMCID: PMC10537601 DOI: 10.1128/jvi.00790-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 06/18/2023] [Indexed: 08/24/2023] Open
Abstract
Bats carry genetically diverse severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Some of them utilize human angiotensin-converting enzyme 2 (hACE2) as a receptor and cannot efficiently replicate in wild-type mice. Our previous study demonstrated that the bat SARSr-CoV rRsSHC014S induces respiratory infection and lung damage in hACE2 transgenic mice but not wild-type mice. In this study, we generated a mouse-adapted strain of rRsSHC014S, which we named SMA1901, by serial passaging of wild-type virus in BALB/c mice. SMA1901 showed increased infectivity in mouse lungs and induced interstitial lung pneumonia in both young and aged mice after intranasal inoculation. Genome sequencing revealed mutations in not only the spike protein but the whole genome, which may be responsible for the enhanced pathogenicity of SMA1901 in wild-type BALB/c mice. SMA1901 induced age-related mortality similar to that observed in SARS and COVID-19. Drug testing using antibodies and antiviral molecules indicated that this mouse-adapted virus strain can be used to test prophylactic and therapeutic drug candidates against SARSr-CoVs. IMPORTANCE The genetic diversity of SARSr-CoVs in wildlife and their potential risk of cross-species infection highlights the importance of developing a powerful animal model to evaluate the antibodies and antiviral drugs. We acquired the mouse-adapted strain of a bat-origin coronavirus named SMA1901 by natural serial passaging of rRsSHC014S in BALB/c mice. The SMA1901 infection caused interstitial pneumonia and inflammatory immune responses in both young and aged BALB/c mice after intranasal inoculation. Our model exhibited age-related mortality similar to SARS and COVID-19. Therefore, our model will be of high value for investigating the pathogenesis of bat SARSr-CoVs and could serve as a prospective test platform for prophylactic and therapeutic candidates.
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Affiliation(s)
- Hao-Feng Lin
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Mei-Qin Liu
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ren-Di Jiang
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Qian-Chun Gong
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
| | - Jia Su
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zi-Shuo Guo
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ying Chen
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jing-Kun Jia
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Tian-Yi Dong
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yan Zhu
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Ang Li
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xu-Rui Shen
- Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, Guangdong, China
| | - Yi Wang
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Bei Li
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Ting-Ting Xie
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xing-Lou Yang
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Ben Hu
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Zheng-Li Shi
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
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14
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Afewerki S, Stocco TD, Rosa da Silva AD, Aguiar Furtado AS, Fernandes de Sousa G, Ruiz-Esparza GU, Webster TJ, Marciano FR, Strømme M, Zhang YS, Lobo AO. In vitro high-content tissue models to address precision medicine challenges. Mol Aspects Med 2023; 91:101108. [PMID: 35987701 PMCID: PMC9384546 DOI: 10.1016/j.mam.2022.101108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/29/2022] [Accepted: 07/20/2022] [Indexed: 01/18/2023]
Abstract
The field of precision medicine allows for tailor-made treatments specific to a patient and thereby improve the efficiency and accuracy of disease prevention, diagnosis, and treatment and at the same time would reduce the cost, redundant treatment, and side effects of current treatments. Here, the combination of organ-on-a-chip and bioprinting into engineering high-content in vitro tissue models is envisioned to address some precision medicine challenges. This strategy could be employed to tackle the current coronavirus disease 2019 (COVID-19), which has made a significant impact and paradigm shift in our society. Nevertheless, despite that vaccines against COVID-19 have been successfully developed and vaccination programs are already being deployed worldwide, it will likely require some time before it is available to everyone. Furthermore, there are still some uncertainties and lack of a full understanding of the virus as demonstrated in the high number new mutations arising worldwide and reinfections of already vaccinated individuals. To this end, efficient diagnostic tools and treatments are still urgently needed. In this context, the convergence of bioprinting and organ-on-a-chip technologies, either used alone or in combination, could possibly function as a prominent tool in addressing the current pandemic. This could enable facile advances of important tools, diagnostics, and better physiologically representative in vitro models specific to individuals allowing for faster and more accurate screening of therapeutics evaluating their efficacy and toxicity. This review will cover such technological advances and highlight what is needed for the field to mature for tackling the various needs for current and future pandemics as well as their relevancy towards precision medicine.
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Affiliation(s)
- Samson Afewerki
- Division of Nanotechnology and Functional Materials, Department of Materials Science and Engineering, Ångström Laboratory, Uppsala University, BOX 35, 751 03, Uppsala, Sweden
| | - Thiago Domingues Stocco
- Bioengineering Program, Technological and Scientific Institute, Brazil University, 08230-030, São Paulo, SP, Brazil; Faculty of Medical Sciences, Unicamp - State University of Campinas, 13083-877, Campinas, SP, Brazil
| | | | - André Sales Aguiar Furtado
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Gustavo Fernandes de Sousa
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Guillermo U Ruiz-Esparza
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA; Division of Health Sciences and Technology, Harvard University ‑ Massachusetts Institute of Technology, Boston, MA, 02115, USA
| | - Thomas J Webster
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil; Hebei University of Technology, Tianjin, China
| | - Fernanda R Marciano
- Department of Physics, Federal University of Piauí (UFPI), Teresina, PI, Brazil
| | - Maria Strømme
- Division of Nanotechnology and Functional Materials, Department of Materials Science and Engineering, Ångström Laboratory, Uppsala University, BOX 35, 751 03, Uppsala, Sweden
| | - Yu Shrike Zhang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA; Division of Health Sciences and Technology, Harvard University ‑ Massachusetts Institute of Technology, Boston, MA, 02115, USA.
| | - Anderson Oliveira Lobo
- Interdisciplinary Laboratory for Advanced Materials, BioMatLab, Department of Materials Engineering, Federal University of Piauí (UFPI), Teresina, PI, Brazil.
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15
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Pechous RD, Malaviarachchi PA, Banerjee SK, Byrum SD, Alkam DH, Ghaffarieh A, Kurten RC, Kennedy JL, Zhang X. An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.18.537373. [PMID: 37131640 PMCID: PMC10153187 DOI: 10.1101/2023.04.18.537373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where the human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an ex vivo human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors, reflecting the heterogeneity of human populations. In particular, two cytokines (IP-10 and IL-8) were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei , not only inhibited virus replication but also production of pro-inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs. SIGNIFICANCE Here we established an ex vivo human precision-cut lung slice platform for assessing SARS-CoV-2 infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe COVID-19, and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.
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16
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Clever S, Volz A. Mouse models in COVID-19 research: analyzing the adaptive immune response. Med Microbiol Immunol 2023; 212:165-183. [PMID: 35661253 PMCID: PMC9166226 DOI: 10.1007/s00430-022-00735-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022]
Abstract
The emergence of SARS-CoV-2, the severe acute respiratory syndrome coronavirus type 2 causing the COVID-19 pandemic, resulted in a major necessity for scientific countermeasures. Investigations revealing the exact mechanisms of the SARS-CoV-2 pathogenesis provide the basis for the development of therapeutic measures and protective vaccines against COVID-19. Animal models are inevitable for infection and pre-clinical vaccination studies as well as therapeutic testing. A well-suited animal model, mimicking the pathology seen in human COVID-19 patients, is an important basis for these investigations. Several animal models were already used during SARS-CoV-2 studies with different clinical outcomes after SARS-CoV-2 infection. Here, we give an overview of different animal models used in SARS-CoV-2 infection studies with a focus on the mouse model. Mice provide a well-established animal model for laboratory use and several different mouse models have been generated and are being used in SARS-CoV-2 studies. Furthermore, the analysis of SARS-CoV-2-specific T cells during infection and in vaccination studies in mice is highlighted.
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Affiliation(s)
- Sabrina Clever
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
| | - Asisa Volz
- Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany
- Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany
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17
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McCollum C, Courtney CM, O’Connor NJ, Aunins TR, Jordan TX, Rogers KL, Brindley S, Brown JM, Nagpal P, Chatterjee A. Safety and Biodistribution of Nanoligomers Targeting the SARS-CoV-2 Genome for the Treatment of COVID-19. ACS Biomater Sci Eng 2023; 9:1656-1671. [PMID: 36853144 PMCID: PMC10000012 DOI: 10.1021/acsbiomaterials.2c00669] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 02/13/2023] [Indexed: 03/01/2023]
Abstract
As the world braces to enter its fourth year of the coronavirus disease 2019 (COVID-19) pandemic, the need for accessible and effective antiviral therapeutics continues to be felt globally. The recent surge of Omicron variant cases has demonstrated that vaccination and prevention alone cannot quell the spread of highly transmissible variants. A safe and nontoxic therapeutic with an adaptable design to respond to the emergence of new variants is critical for transitioning to the treatment of COVID-19 as an endemic disease. Here, we present a novel compound, called SBCoV202, that specifically and tightly binds the translation initiation site of RNA-dependent RNA polymerase within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, inhibiting viral replication. SBCoV202 is a Nanoligomer, a molecule that includes peptide nucleic acid sequences capable of binding viral RNA with single-base-pair specificity to accurately target the viral genome. The compound has been shown to be safe and nontoxic in mice, with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed using three separate administration methods, namely, intranasal, intravenous, and intraperitoneal. Safety studies showed the Nanoligomer caused no outward distress, immunogenicity, or organ tissue damage, measured through observation of behavior and body weight, serum levels of cytokines, and histopathology of fixed tissue, respectively. SBCoV202 was evenly biodistributed throughout the body, with most tissues measuring Nanoligomer concentrations well above the compound KD of 3.37 nM. In addition to favorable availability to organs such as the lungs, lymph nodes, liver, and spleen, the compound circulated through the blood and was rapidly cleared through the renal and urinary systems. The favorable biodistribution and lack of immunogenicity and toxicity set Nanoligomers apart from other antisense therapies, while the adaptability of the nucleic acid sequence of Nanoligomers provides a defense against future emergence of drug resistance, making these molecules an attractive potential treatment for COVID-19.
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Affiliation(s)
- Colleen
R. McCollum
- Department
of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80303, United States
| | - Colleen M. Courtney
- Department
of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80303, United States
- Sachi Bio, Colorado Technology Center, Louisville, Colorado 80027, United States
| | - Nolan J. O’Connor
- Department
of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80303, United States
| | - Thomas R. Aunins
- Department
of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80303, United States
| | - Tristan X. Jordan
- Department
of Microbiology, New York University Langone, New York, New York 10016, United States
| | - Keegan L. Rogers
- Department
of Pharmaceutical Sciences, University of
Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States
| | - Stephen Brindley
- Department
of Pharmaceutical Sciences, University of
Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States
| | - Jared M. Brown
- Department
of Pharmaceutical Sciences, University of
Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States
| | - Prashant Nagpal
- Sachi Bio, Colorado Technology Center, Louisville, Colorado 80027, United States
- Antimicrobial
Regeneration Consortium Labs, Louisville, Colorado 80027, United States
| | - Anushree Chatterjee
- Department
of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado 80303, United States
- Sachi Bio, Colorado Technology Center, Louisville, Colorado 80027, United States
- Antimicrobial
Regeneration Consortium Labs, Louisville, Colorado 80027, United States
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18
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Mukherjee AG, Wanjari UR, Kannampuzha S, Das S, Murali R, Namachivayam A, Renu K, Ramanathan G, Doss C GP, Vellingiri B, Dey A, Valsala Gopalakrishnan A. The pathophysiological and immunological background of the monkeypox virus infection: An update. J Med Virol 2023; 95:e28206. [PMID: 36217803 DOI: 10.1002/jmv.28206] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/03/2022] [Accepted: 10/06/2022] [Indexed: 01/18/2023]
Abstract
In addition to the COVID-19 waves, the globe is facing global monkeypox (MPX) outbreak. MPX is an uncommon zoonotic infection characterized by symptoms similar to smallpox. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the genus Orthopoxvirus (OPXV). MPXV, which causes human disease, has been confined to Africa for many years, with only a few isolated cases in other areas. Outside of Africa, the continuing MPXV outbreak in multiple countries in 2022 is the greatest in recorded history. The current outbreak, with over 10 000 confirmed cases in over 50 countries between May and July 2022, demonstrates that MPXV may travel rapidly among humans and pose a danger to human health worldwide. The rapid spread of such outbreaks in recent times has elevated MPX to the status of a rising zoonotic disease with significant epidemic potential. While the MPXV is not as deadly or contagious as the variola virus that causes smallpox, it poses a threat because it could evolve into a more potent human pathogen. This review assesses the potential threat to the human population and provides a brief overview of what is currently known about this reemerging virus. By analyzing the biological effects of MPXV on human health, its shifting epidemiological footprint, and currently available therapeutic options, this review has presented the most recent insights into the biology of the virus. This study also clarifies the key potential causes that could be to blame for the present MPX outbreak and draw attention to major research questions and promising new avenues for combating the current MPX epidemic.
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Affiliation(s)
- Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Sandra Kannampuzha
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Soumik Das
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Reshma Murali
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Arunraj Namachivayam
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Kaviyarasi Renu
- Department of Biochemistry, Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India
| | - Gnanasambandan Ramanathan
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - George Priya Doss C
- Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
| | - Balachandar Vellingiri
- Department of Human Genetics and Molecular Biology, Human Molecular Cytogenetics and Stem Cell Laboratory, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata, West Bengal, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT), Vellore, Tamil Nadu, India
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19
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Hadizadeh N, Naderi M, Khezri J, Yazdani M, Shamsara M, Hashemi E. Appraisal of SARS-CoV-2 mutations and their impact on vaccination efficacy: an overview. J Diabetes Metab Disord 2022; 21:1763-1783. [PMID: 35891981 PMCID: PMC9305048 DOI: 10.1007/s40200-022-01002-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 02/07/2022] [Indexed: 12/02/2022]
Abstract
With the unexpected emergence of the novel 2019 Wuhan coronavirus, the world was faced with a sudden uproar that quickly shifted into a serious life-threatening pandemic. Affecting the lives of the global population and leaving drastic damage in various sections and systems, several measures have been constantly taken to tackle down this crisis. For instance, numerous vaccines have been developed in the past two years, some of which have been granted emergency use, thus providing sufficient immunity to the vaccinated individuals. However, the appearance of newly emerged SARS-CoV-2 variants with accelerated transmission and fatality has led the world towards another pandemic. Having undergone various mutations in genomic and/or amino acid profiles, some of the emerged variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta have displayed immune evasion and pathogenicity even in the vaccinated population, hence raising concerns regarding the efficacy of current vaccines against new VOCs of COVID-19. Therefore, genomic investigations of SARS-CoV-2 mutations are expected to provide valuable insight into the evolution of SARS-CoV-2, while also determining the impact of different mutations on infection severity. This study was constructed with the aim of shining light on recent advances regarding mutations in major COVID-19 VOCs, as well as vaccination efficacy against those VOCs.
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Affiliation(s)
- Nastaran Hadizadeh
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mousa Naderi
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box: 14965-16, Tehran, Iran
| | - Jafar Khezri
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box: 14965-16, Tehran, Iran
| | - Meysam Yazdani
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box: 14965-16, Tehran, Iran
| | - Mehdi Shamsara
- Department of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O. Box: 14965-16, Tehran, Iran
- National Research Centre for Transgenic Mouse, National Institute of Genetic Engineering and Biotechnology, P.O. Box: 14965-161, Tehran, Iran
| | - Ehsan Hashemi
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- National Research Centre for Transgenic Mouse, National Institute of Genetic Engineering and Biotechnology, P.O. Box: 14965-161, Tehran, Iran
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20
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Leneva IA, Smirnova DI, Kartashova NP, Gracheva AV, Ivanina AV, Glubokova EA, Korchevaya ER, Pancratov AA, Trunova GV, Khokhlova VA, Svitich OA, Zverev VV, Faizuloev EB. [Comparative study of Wuhan-like and omicron-like variants of SARS-CoV-2 in experimental animal models]. Vopr Virusol 2022; 67:439-449. [PMID: 36515289 DOI: 10.36233/0507-4088-135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Indexed: 12/05/2022]
Abstract
INTRODUCTION The variability of SARS-CoV-2 appeared to be higher than expected, the emergence of new variants raises concerns. The aim of the work was to compare the pathogenicity of the Wuhan and BA.1.1/Omicron variants in BALB/c mice and Syrian hamsters. MATERIALS AND METHODS The study used strains of SARS-CoV-2: Dubrovka phylogenetically close to Wuhan-Hu-1, and LIA phylogenetically close to Omicron, BALB/c mice, transgenic mice B6.Cg-Tg(K18-ACE2)2Prlmn/HEMI Hemizygous for Tg(K18-ACE2)2Prlmn, Syrian golden hamsters. Animals were infected intranasally, pathogenicity was estimated by a complex of clinical, pathomorphological and virological methods. RESULTS Comparative studies of SARS-CoV-2 Dubrovka and LIA strains on animal models demonstrated their heterogeneous pathogenicity. In parallel infection of BALB/c mice with Dubrovka and LIA variants, the infection proceeded without serious clinical signs and lung damage. Infection with the LIA strain resulted to a systemic disease with a high concentration of viral RNA in the lungs and brain tissues of animals. The presence of viral RNA in mice infected with the Dubrovka strain was transient and undetectable in the lungs by day 7 post-infection. Unlike the mouse model, in hamsters, the Dubrovka strain had a greater pathogenicity than the LIA strain. In hamsters infected with the Dubrovka strain lung lesions were more significant, and the virus spread through organs, in particular in brain tissue, was observed. In hamsters infected with the LIA strain virus was not detected in brain tissue. CONCLUSION The study of various variants of SARS-CoV-2 in species initially unsusceptible to SARS-CoV-2 infection is important for monitoring zoonotic reservoirs that increase the risk of spread of new variants in humans.
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Affiliation(s)
- I A Leneva
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - D I Smirnova
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - N P Kartashova
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - A V Gracheva
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - A V Ivanina
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - E A Glubokova
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - E R Korchevaya
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - A A Pancratov
- Herzen Moscow Research Institute of Oncology of the Ministry of Health of Russia
| | - G V Trunova
- Herzen Moscow Research Institute of Oncology of the Ministry of Health of Russia
| | - V A Khokhlova
- Herzen Moscow Research Institute of Oncology of the Ministry of Health of Russia
| | - O A Svitich
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - V V Zverev
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
| | - E B Faizuloev
- Mechnikov Research Institute of Vaccines and Sera, Department of Virology
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21
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Narasimhan H, Wu Y, Goplen NP, Sun J. Immune determinants of chronic sequelae after respiratory viral infection. Sci Immunol 2022; 7:eabm7996. [DOI: 10.1126/sciimmunol.abm7996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The acute effects of various respiratory viral infections have been well studied, with extensive characterization of the clinical presentation as well as viral pathogenesis and host responses. However, over the course of the recent COVID-19 pandemic, the incidence and prevalence of chronic sequelae after acute viral infections have become increasingly appreciated as a serious health concern. Post-acute sequelae of COVID-19, alternatively described as “long COVID-19,” are characterized by symptoms that persist for longer than 28 days after recovery from acute illness. Although there exists substantial heterogeneity in the nature of the observed sequelae, this phenomenon has also been observed in the context of other respiratory viral infections including influenza virus, respiratory syncytial virus, rhinovirus, severe acute respiratory syndrome coronavirus, and Middle Eastern respiratory syndrome coronavirus. In this Review, we discuss the various sequelae observed following important human respiratory viral pathogens and our current understanding of the immunological mechanisms underlying the failure of restoration of homeostasis in the lung.
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Affiliation(s)
- Harish Narasimhan
- Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Yue Wu
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Nick P. Goplen
- Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, MN 55905, USA
| | - Jie Sun
- Carter Immunology Center, University of Virginia, Charlottesville, VA 22908, USA
- Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
- Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
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22
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Lin Q, Lu C, Hong Y, Li R, Chen J, Chen W, Chen J. Animal models for studying coronavirus infections and developing antiviral agents and vaccines. Antiviral Res 2022; 203:105345. [PMID: 35605699 PMCID: PMC9122840 DOI: 10.1016/j.antiviral.2022.105345] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/30/2022] [Accepted: 05/17/2022] [Indexed: 01/17/2023]
Abstract
In addition to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 has become the third deadly coronavirus that infects humans and causes the new coronavirus disease (COVID-19). COVID-19 has already caused more than six million deaths worldwide and it is likely the biggest pandemic of this century faced by mankind. Although many studies on SARS-CoV-2 have been conducted, a detailed understanding of SARS-CoV-2 and COVID-19 is still lacking. Animal models are indispensable for studying its pathogenesis and developing vaccines and antivirals. In this review, we analyze animal models of coronavirus infections and explore their applications on antivirals and vaccines.
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Affiliation(s)
- Qisheng Lin
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Chunni Lu
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Monash University, Clayton, Victoria 3168, Australia
| | - Yuqi Hong
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Runfeng Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China
| | - Jinding Chen
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Weisan Chen
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, 3086, Australia.
| | - Jianxin Chen
- Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
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23
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Ding Z, Chen T, Lan J, Wong G. Application of animal models to compare and contrast the virulence of current and future potential SARS-CoV-2 variants. BIOSAFETY AND HEALTH 2022; 4:154-160. [PMID: 35528630 PMCID: PMC9069976 DOI: 10.1016/j.bsheal.2022.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/01/2022] [Accepted: 05/01/2022] [Indexed: 02/07/2023] Open
Abstract
Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified during late 2019, the sustained spread of this pathogen within the human population has caused worldwide disruption with staggering infection rates and death tolls. Due to the accumulation of mutations in SARS-CoV-2, the virus has evolved into many variants, five of which have been listed as variants of concern VOCs by the World Health Organization (WHO). Multiple animal models of SARS-CoV-2 have been developed to evaluate vaccines and drugs and to assess the pathogenicity, transmissibility and antiviral measures of these VOCs. Here, we review the cutting-edge research based on mouse, hamster, ferret and non-human primate models for evaluating SARS-CoV-2 with a focus on the Omicron variant, and highlight the importance of updating vaccines in a timely manner in order to mitigate the negative effects of SARS-CoV-2 infections in the human population.
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Affiliation(s)
- Zhe Ding
- Viral Hemorrhagic Fevers Research Unit, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
- University of Chinese Academy of Sciences, Beijing 100190, China
| | - Tong Chen
- Viral Hemorrhagic Fevers Research Unit, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
- University of Chinese Academy of Sciences, Beijing 100190, China
| | - Jiaming Lan
- Viral Hemorrhagic Fevers Research Unit, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Gary Wong
- Viral Hemorrhagic Fevers Research Unit, CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
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24
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Zhang Y, Wang Q, Mackay CR, Ng LG, Kwok I. Neutrophil subsets and their differential roles in viral respiratory diseases. J Leukoc Biol 2022; 111:1159-1173. [PMID: 35040189 PMCID: PMC9015493 DOI: 10.1002/jlb.1mr1221-345r] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/28/2021] [Accepted: 01/04/2022] [Indexed: 12/19/2022] Open
Abstract
Neutrophils play significant roles in immune homeostasis and as neutralizers of microbial infections. Recent evidence further suggests heterogeneity of neutrophil developmental and activation states that exert specialized effector functions during inflammatory disease conditions. Neutrophils can play multiple roles during viral infections, secreting inflammatory mediators and cytokines that contribute significantly to host defense and pathogenicity. However, their roles in viral immunity are not well understood. In this review, we present an overview of neutrophil heterogeneity and its impact on the course and severity of viral respiratory infectious diseases. We focus on the evidence demonstrating the crucial roles neutrophils play in the immune response toward respiratory infections, using influenza as a model. We further extend the understanding of neutrophil function with the studies pertaining to COVID-19 disease and its neutrophil-associated pathologies. Finally, we discuss the relevance of these results for future therapeutic options through targeting and regulating neutrophil-specific responses.
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Affiliation(s)
- Yuning Zhang
- Department of ResearchNational Skin CentreSingaporeSingapore
| | - Quanbo Wang
- School of Pharmaceutical Sciences, Shandong Analysis and Test CenterQilu University of Technology (Shandong Academy of Sciences)JinanChina
| | - Charles R Mackay
- School of Pharmaceutical Sciences, Shandong Analysis and Test CenterQilu University of Technology (Shandong Academy of Sciences)JinanChina
- Department of Microbiology, Infection and Immunity ProgramBiomedicine Discovery Institute, Monash UniversityMelbourneAustralia
| | - Lai Guan Ng
- Singapore Immunology Network (SIgN)A*STAR (Agency for Science, Technology and Research)BiopolisSingapore
- State Key Laboratory of Experimental HematologyInstitute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical CollegeTianjinChina
- School of Biological SciencesNanyang Technological UniversitySingaporeSingapore
- Department of Microbiology and ImmunologyImmunology Translational Research Program, Yong Loo Lin School of Medicine, Immunology Program, Life Sciences Institute, National University of SingaporeSingaporeSingapore
- National Cancer Centre SingaporeSingaporeSingapore
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN)A*STAR (Agency for Science, Technology and Research)BiopolisSingapore
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25
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Singh DK, Cole J, Escobedo RA, Alfson KJ, Singh B, Lee TH, Alvarez X, Ganatra SR, Carrion R, Kaushal D. Animal Models of COVID-19: Nonhuman Primates. Methods Mol Biol 2022; 2452:227-258. [PMID: 35554911 DOI: 10.1007/978-1-0716-2111-0_15] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
With the advent of the novel SARS-CoV-2, the entire world has been thrown into chaos with severe disruptions from a normal life. While the entire world was going chaotic, the researchers throughout the world were struggling to contribute to the best of their capabilities to advance the understanding of this new pandemic and fast track the development of novel therapeutics and vaccines. While various animal models have helped a lot to understand the basic physiology, nonhman primates have been promising and much more successful in modelling human diseases compared to other available clinical models. Here we describe the different aspects of modelling the SARS-CoV-2 infection in NHPs along with the associated methods used in NHP immunology.
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Affiliation(s)
- Dhiraj K Singh
- Southwest National Primate Research Center, San Antonio, TX, USA
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Journey Cole
- Southwest National Primate Research Center, San Antonio, TX, USA
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Ruby A Escobedo
- Southwest National Primate Research Center, San Antonio, TX, USA
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | | | - Bindu Singh
- Southwest National Primate Research Center, San Antonio, TX, USA
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Tae-Hyung Lee
- Southwest National Primate Research Center, San Antonio, TX, USA
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Xavier Alvarez
- Southwest National Primate Research Center, San Antonio, TX, USA
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Shashank R Ganatra
- Southwest National Primate Research Center, San Antonio, TX, USA
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | | | - Deepak Kaushal
- Southwest National Primate Research Center, San Antonio, TX, USA.
- Texas Biomedical Research Institute, San Antonio, TX, USA.
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26
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Xie P, Fang Y, Baloch Z, Yu H, Zhao Z, Li R, Zhang T, Li R, Zhao J, Yang Z, Dong S, Xia X. A Mouse-Adapted Model of HCoV-OC43 and Its Usage to the Evaluation of Antiviral Drugs. Front Microbiol 2022; 13:845269. [PMID: 35755996 PMCID: PMC9220093 DOI: 10.3389/fmicb.2022.845269] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 04/19/2022] [Indexed: 11/24/2022] Open
Abstract
The human coronavirus OC43 (HCoV-OC43) is one of the most common causes of common cold but can lead to fatal pneumonia in children and elderly. However, the available animal models of HCoV-OC43 did not show respiratory symptoms that are insufficient to assist in screening antiviral agents for respiratory diseases. In this study, we adapted the HCoV-OC43 VR-1558 strain by serial passage in suckling C57BL/6 mice and the resulting mouse-adapted virus at passage 9 (P9) contained 8 coding mutations in polyprotein 1ab, spike (S) protein, and nucleocapsid (N) protein. Pups infected with the P9 virus significantly lost body weight and died within 5 dpi. In cerebral and pulmonary tissues, the P9 virus replication induced the production of G-CSF, IFN-γ, IL-6, CXCL1, MCP-1, MIP-1α, RANTES, IP-10, MIP-1β, and TNF-α, as well as pathological alterations including reduction of neuronal cells and typical symptoms of viral pneumonia. We found that the treatment of arbidol hydrochloride (ARB) or Qingwenjiere Mixture (QJM) efficiently improved the symptoms and decreased n gene expression, inflammatory response, and pathological changes. Furthermore, treating with QJM or ARB raised the P9-infected mice's survival rate within a 15 day observation period. These findings suggested that the new mouse-adapted HCoV-OC43 model is applicable and reproducible for antiviral studies of HCoV-OC43.
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Affiliation(s)
- Peifang Xie
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Yue Fang
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Zulqarnain Baloch
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Huanhuan Yu
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Zeyuan Zhao
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Rongqiao Li
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Tongtong Zhang
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Runfeng Li
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jincun Zhao
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zifeng Yang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shuwei Dong
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
| | - Xueshan Xia
- The Affiliated AnNing First Hospital, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China
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27
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Hamsters Expressing Human Angiotensin-Converting Enzyme 2 Develop Severe Disease following Exposure to SARS-CoV-2. mBio 2022; 13:e0290621. [PMID: 35073750 PMCID: PMC8787465 DOI: 10.1128/mbio.02906-21] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a global health emergency. While most human disease is mild to moderate, some infections lead to a severe disease characterized by acute respiratory distress, hypoxia, anosmia, ageusia, and, in some instances, neurological involvement. Small-animal models reproducing severe disease, including neurological sequela, are needed to characterize the pathophysiological mechanism(s) of disease and to identify medical countermeasures. Transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) viral receptor under the control of the K18 promoter develop severe and lethal respiratory disease subsequent to SARS-CoV-2 intranasal challenge when high viral doses are used. Here, we report on SARS-CoV-2 infection of hamsters engineered to express the hACE2 receptor under the control of the K18 promoter. K18-hACE2 hamsters infected with a relatively low dose of 100 or 1,000 PFU of SARS-CoV-2 developed a severe and lethal disease, with most animals succumbing by day 5 postinfection. Hamsters developed severe lesions and inflammation within the upper and lower respiratory system, including infection of the nasal cavities causing marked destruction of the olfactory epithelium as well as severe bronchopneumonia that extended deep into the alveoli. Additionally, SARS-CoV-2 infection spread to the central nervous system (CNS), including the brain stem and spinal cord. Wild-type (WT) hamsters naturally support SARS-CoV-2 infection, with the primary lesions present in the respiratory tract and nasal cavity. Overall, infection in the K18-hACE2 hamsters is more extensive than that in WT hamsters, with more CNS involvement and a lethal outcome. These findings demonstrate the K18-hACE2 hamster model will be valuable for studying SARS-CoV-2. IMPORTANCE The rapid emergence of SARS-CoV-2 has created a global health emergency. While most human SARS-CoV-2 disease is mild, some people develop severe, life-threatening disease. Small-animal models mimicking the severe aspects of human disease are needed to more clearly understand the pathophysiological processes driving this progression. Here, we studied SARS-CoV-2 infection in hamsters engineered to express the human angiotensin-converting enzyme 2 viral receptor under the control of the K18 promoter. SARS-CoV-2 produces a severe and lethal infection in transgenic hamsters that mirrors the most severe aspects of COVID-19 in humans, including respiratory and neurological injury. In contrast to other animal systems, hamsters manifest disease with levels of input virus more consistent with natural human infection. This system will be useful for the study of SARS-CoV-2 disease and the development of drugs targeting this virus.
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Bednash JS, Kagan VE, Englert JA, Farkas D, Tyurina YY, Tyurin VA, Samovich SN, Farkas L, Elhance A, Johns F, Lee H, Cheng L, Majumdar A, Jones D, Mejia OR, Ruane-Foster M, Londino JD, Mallampalli RK, Robinson RT. Syrian hamsters as a model of lung injury with SARS-CoV-2 infection: Pathologic, physiologic, and detailed molecular profiling. Transl Res 2022; 240:1-16. [PMID: 34740873 PMCID: PMC8562047 DOI: 10.1016/j.trsl.2021.10.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 12/16/2022]
Abstract
The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. Knowledge of molecular mechanisms driving host responses to SARS-CoV-2 is limited by the lack of reliable preclinical models of COVID-19 that recapitulate human illness. Further, existing COVID-19 animal models are not characterized as models of experimental acute lung injury (ALI) or ARDS. Acknowledging differences in experimental lung injury in animal models and human ARDS, here we systematically evaluate a model of experimental acute lung injury as a result of SARS-CoV-2 infection in Syrian golden hamsters. Following intranasal inoculation, hamsters demonstrate acute SARS-CoV-2 infection, viral pneumonia, and systemic illness but survive infection with clearance of virus. Hamsters exposed to SARS-CoV-2 exhibited key features of experimental ALI, including histologic evidence of lung injury, increased pulmonary permeability, acute inflammation, and hypoxemia. RNA sequencing of lungs indicated upregulation of inflammatory mediators that persisted after infection clearance. Lipidomic analysis demonstrated significant differences in hamster phospholipidome with SARS-CoV-2 infection. Lungs infected with SARS-CoV-2 showed increased apoptosis and ferroptosis. Thus, SARS-CoV-2 infected hamsters exhibit key features of experimental lung injury supporting their use as a preclinical model of COVID-19 ARDS.
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Key Words
- ards, acute respiratory distress syndrome
- ali, acute lung injury
- covid-19, coronavirus disease 2019
- sars-cov-2, severe acute respiratory syndrome coronavirus-2
- ace2, angiotensin converting enzyme 2
- bal, bronchoalveolar lavage
- ifit, inf-induced protein with tetratricopeptide repeats
- ifn, interferon
- ihc, immunohistochemistry
- il, interleukin
- mpo, myeloperoxidase
- ngs, next generation sequencing
- opls-da, orthogonal projection of latent structures - discriminate analysis
- pc, phosphatidylcholine
- pe, phosphatidylethanolamine
- pfu, plaque forming unit
- pla2, phospholipase a2
- tfrc, transferrin receptor protein 1
- vip, variable importance in projection
- voc, variant of concern
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Affiliation(s)
- Joseph S Bednash
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio.
| | - Valerian E Kagan
- Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Joshua A Englert
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Daniela Farkas
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Yulia Y Tyurina
- Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Vladimir A Tyurin
- Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Svetlana N Samovich
- Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Laszlo Farkas
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Ajit Elhance
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Finny Johns
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Hyunwook Lee
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Lijun Cheng
- Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio
| | - Abhishek Majumdar
- Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio
| | - Daniel Jones
- The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Oscar Rosas Mejia
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio
| | - Marisa Ruane-Foster
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio
| | - James D Londino
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Rama K Mallampalli
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio
| | - Richard T Robinson
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio.
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29
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Saravanan UB, Namachivayam M, Jeewon R, Huang JD, Durairajan SSK. Animal models for SARS-CoV-2 and SARS-CoV-1 pathogenesis, transmission and therapeutic evaluation. World J Virol 2022; 11:40-56. [PMID: 35117970 PMCID: PMC8788210 DOI: 10.5501/wjv.v11.i1.40] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/22/2021] [Accepted: 11/24/2021] [Indexed: 02/06/2023] Open
Abstract
There is a critical need to develop animal models to alleviate vaccine and drug development difficulties against zoonotic viral infections. The coronavirus family, which includes severe acute respiratory syndrome coronavirus 1 and severe acute respiratory syndrome coronavirus 2, crossed the species barrier and infected humans, causing a global outbreak in the 21st century. Because humans do not have pre-existing immunity against these viral infections and with ethics governing clinical trials, animal models are therefore being used in clinical studies to facilitate drug discovery and testing efficacy of vaccines. The ideal animal models should reflect the viral replication, clinical signs, and pathological responses observed in humans. Different animal species should be tested to establish an appropriate animal model to study the disease pathology, transmission and evaluation of novel vaccine and drug candidates to treat coronavirus disease 2019. In this context, the present review summarizes the recent progress in developing animal models for these two pathogenic viruses and highlights the utility of these models in studying SARS-associated coronavirus diseases.
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Affiliation(s)
- Udhaya Bharathy Saravanan
- Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur 610005, India
| | - Mayurikaa Namachivayam
- Department of Microbiology, School of Life Sciences, Central University of Tamil Nadu, Tiruvarur 610005, India
| | - Rajesh Jeewon
- Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Reduit 80837, Mauritius
| | - Jian-Dong Huang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
- CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, Guangdong Province, China
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30
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Gosavi D, Cheatham B, Sztuba-Solinska J. Label-Free Detection of Human Coronaviruses in Infected Cells Using Enhanced Darkfield Hyperspectral Microscopy (EDHM). J Imaging 2022; 8:24. [PMID: 35200727 PMCID: PMC8874371 DOI: 10.3390/jimaging8020024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Human coronaviruses (HCoV) are causative agents of mild to severe intestinal and respiratory infections in humans. In the last 15 years, we have witnessed the emergence of three zoonotic, highly pathogenic HCoVs. Thus, early and accurate detection of these viral pathogens is essential for preventing transmission and providing timely treatment and monitoring of drug resistance. Herein, we applied enhanced darkfield hyperspectral microscopy (EDHM), a novel non-invasive, label-free diagnostic tool, to rapidly and accurately identify two strains of HCoVs, i.e., OC43 and 229E. The EDHM technology allows collecting the optical image with spectral and spatial details in a single measurement without direct contact between the specimen and the sensor. Thus, it can directly map spectral signatures specific for a given viral strain in a complex biological milieu. Our study demonstrated distinct spectral patterns for HCoV-OC43 and HCoV-229E virions in the solution, serving as distinguishable parameters for their differentiation. Furthermore, spectral signatures obtained for both HCoV strains in the infected cells displayed a considerable peak wavelength shift compared to the uninfected cell, indicating that the EDHM is applicable to detect HCoV infection in mammalian cells.
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Affiliation(s)
- Devadatta Gosavi
- Department of Biological Sciences, Auburn University, 120 W. Samford Ave, Rouse Life Sciences Building, Auburn, AL 36849, USA;
| | - Byron Cheatham
- Cytoviva, Inc., 570 Devall Drive Suite 301, Auburn, AL 36832, USA;
| | - Joanna Sztuba-Solinska
- Department of Biological Sciences, Auburn University, 120 W. Samford Ave, Rouse Life Sciences Building, Auburn, AL 36849, USA;
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31
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A Comparative and Comprehensive Review of Antibody Applications in the Treatment of Lung Disease. Life (Basel) 2022; 12:life12010130. [PMID: 35054524 PMCID: PMC8778790 DOI: 10.3390/life12010130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 01/08/2022] [Accepted: 01/10/2022] [Indexed: 11/30/2022] Open
Abstract
Antibodies are a type of protein produced by active B cells in response to antigen stimulation. A series of monoclonal antibodies and neutralizing antibodies have been invented and put into clinical use because of their high therapeutic effect and bright developing insight. Patients with cancer, infectious diseases, and autoimmune diseases can all benefit from antibody therapy. However, the targeting aspects and potential mechanisms for treating these diseases differ. In the treatment of patients with infectious diseases such as COVID-19, neutralizing antibodies have been proposed as reliable vaccines against COVID-19, which target the ACE2 protein by preventing virus entry into somatic cells. Monoclonal antibodies can target immune checkpoints (e.g., PD-L1 and CTLA-4), tyrosine kinase and subsequent signaling pathways (e.g., VEGF), and cytokines in cancer patients (e.g. IL-6 and IL-1β). It is debatable whether there is any connection between the use of antibodies in these diseases. It would be fantastic to discover the related points and explain the burden for the limitation of cross-use of these techniques. In this review, we provided a comprehensive overview of the use of antibodies in the treatment of infectious disease and cancer patients. There are also discussions of their mechanisms and history. In addition, we discussed our future outlook on the use of antibodies.
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32
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Wan D, Du T, Hong W, Chen L, Que H, Lu S, Peng X. Neurological complications and infection mechanism of SARS-COV-2. Signal Transduct Target Ther 2021; 6:406. [PMID: 34815399 PMCID: PMC8609271 DOI: 10.1038/s41392-021-00818-7] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 09/27/2021] [Accepted: 11/02/2021] [Indexed: 02/05/2023] Open
Abstract
Currently, SARS-CoV-2 has caused a global pandemic and threatened many lives. Although SARS-CoV-2 mainly causes respiratory diseases, growing data indicate that SARS-CoV-2 can also invade the central nervous system (CNS) and peripheral nervous system (PNS) causing multiple neurological diseases, such as encephalitis, encephalopathy, Guillain-Barré syndrome, meningitis, and skeletal muscular symptoms. Despite the increasing incidences of clinical neurological complications of SARS-CoV-2, the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established. In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.
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Affiliation(s)
- Dandan Wan
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatricts, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Tingfu Du
- National Kunming High-level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China
| | - Weiqi Hong
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatricts, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Li Chen
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatricts, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Haiying Que
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatricts, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, 610041, Chengdu, Sichuan, PR China
| | - Shuaiyao Lu
- National Kunming High-level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China.
| | - Xiaozhong Peng
- National Kunming High-level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China.
- State Key Laboratory of Medical Molecular Biology, Department of Molecular, Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China.
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33
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Coleman C, Doyle-Meyers LA, Russell-Lodrigue KE, Golden N, Threeton B, Song K, Pierre G, Baribault C, Bohm RP, Maness NJ, Kolls JK, Rappaport J, Mudd JC. Similarities and Differences in the Acute-Phase Response to SARS-CoV-2 in Rhesus Macaques and African Green Monkeys. Front Immunol 2021; 12:754642. [PMID: 34691074 PMCID: PMC8527883 DOI: 10.3389/fimmu.2021.754642] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Understanding SARS-CoV-2 immune pathology is critical for the development of effective vaccines and treatments. Here, we employed unbiased serial whole-blood transcriptome profiling by weighted gene network correlation analysis (WGCNA) at pre-specified timepoints of infection to understand SARS-CoV-2-related immune alterations in a cohort of rhesus macaques (RMs) and African green monkeys (AGMs) presenting with varying degrees of pulmonary pathology. We found that the bulk of transcriptional changes occurred at day 3 post-infection and normalized to pre-infection levels by 3 weeks. There was evidence of coordination of transcriptional networks in blood (defined by WGCNA) and the nasopharyngeal SARS-CoV-2 burden as well as the absolute monocyte count. Pathway analysis of gene modules revealed prominent regulation of type I and type II interferon stimulated genes (ISGs) in both RMs and AGMs, with the latter species exhibiting a greater breadth of ISG upregulation. Notably, pathways relating to neutrophil degranulation were enriched in blood of SARS-CoV-2 infected AGMs, but not RMs. Our results elude to hallmark similarities as well as differences in the RM and AGM acute response to SARS-CoV-2 infection, and may help guide the selection of particular NHP species in modeling aspects of COVID-19 disease outcome.
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Affiliation(s)
- Celeste Coleman
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Lara A Doyle-Meyers
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Kasi E Russell-Lodrigue
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Nadia Golden
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States
| | - Breanna Threeton
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States
| | - Kejing Song
- Center for Translational Research in Infection and Inflammation, Department of Pediatrics and Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Genevieve Pierre
- Center for Translational Research in Infection and Inflammation, Department of Pediatrics and Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Carl Baribault
- Center for Research & Scientific Computing, Tulane University Information Technology, New Orleans, LA, United States
| | - Rudolf P Bohm
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Nicholas J Maness
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jay K Kolls
- Center for Translational Research in Infection and Inflammation, Department of Pediatrics and Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jay Rappaport
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Joseph C Mudd
- Department of Immunology and Microbiology, Tulane National Primate Research Center, Covington, LA, United States.,Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA, United States
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34
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Intradermal-delivered DNA vaccine induces durable immunity mediating a reduction in viral load in a rhesus macaque SARS-CoV-2 challenge model. CELL REPORTS MEDICINE 2021; 2:100420. [PMID: 34604818 PMCID: PMC8479327 DOI: 10.1016/j.xcrm.2021.100420] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 05/25/2021] [Accepted: 09/22/2021] [Indexed: 12/14/2022]
Abstract
Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health and social and economic infrastructures. Here, we assess the immunogenicity and anamnestic protective efficacy in rhesus macaques of an intradermal (i.d.)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800, currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and induced spike antigen and RBD binding antibodies with ADCP and ADCD activity. Sera from the animals neutralized both the D614 and G614 SARS-CoV-2 pseudotype viruses. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T cell and neutralizing antibody responses. These responses were associated with lower viral loads in the lung. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system, which are likely important for providing durable protection against COVID-19 disease.
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35
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Elkashif A, Alhashimi M, Sayedahmed EE, Sambhara S, Mittal SK. Adenoviral vector-based platforms for developing effective vaccines to combat respiratory viral infections. Clin Transl Immunology 2021; 10:e1345. [PMID: 34667600 PMCID: PMC8510854 DOI: 10.1002/cti2.1345] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 09/10/2021] [Accepted: 09/15/2021] [Indexed: 02/06/2023] Open
Abstract
Since the development of the first vaccine against smallpox over two centuries ago, vaccination strategies have been at the forefront of significantly impacting the incidences of infectious diseases globally. However, the increase in the human population, deforestation and climate change, and the rise in worldwide travel have favored the emergence of new viruses with the potential to cause pandemics. The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a cruel reminder of the impact of novel pathogens and the suboptimal capabilities of conventional vaccines. Therefore, there is an urgent need to develop new vaccine strategies that allow the production of billions of doses in a short duration and are broadly protective against emerging and re-emerging infectious diseases. Extensive knowledge of the molecular biology and immunology of adenoviruses (Ad) has favored Ad vectors as platforms for vaccine design. The Ad-based vaccine platform represents an attractive strategy as it induces robust humoral and cell-mediated immune responses and can meet the global demand in a pandemic situation. This review describes the status of Ad vector-based vaccines in preclinical and clinical studies for current and emerging respiratory viruses, particularly coronaviruses, influenza viruses and respiratory syncytial viruses.
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Affiliation(s)
- Ahmed Elkashif
- Department of Comparative PathobiologyPurdue Institute for Inflammation, Immunology and Infectious Disease, and Purdue University Center for Cancer ResearchCollege of Veterinary MedicinePurdue UniversityWest LafayetteINUSA
| | - Marwa Alhashimi
- Department of Comparative PathobiologyPurdue Institute for Inflammation, Immunology and Infectious Disease, and Purdue University Center for Cancer ResearchCollege of Veterinary MedicinePurdue UniversityWest LafayetteINUSA
| | - Ekramy E Sayedahmed
- Department of Comparative PathobiologyPurdue Institute for Inflammation, Immunology and Infectious Disease, and Purdue University Center for Cancer ResearchCollege of Veterinary MedicinePurdue UniversityWest LafayetteINUSA
| | | | - Suresh K Mittal
- Department of Comparative PathobiologyPurdue Institute for Inflammation, Immunology and Infectious Disease, and Purdue University Center for Cancer ResearchCollege of Veterinary MedicinePurdue UniversityWest LafayetteINUSA
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36
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Yaqub N, Wayne G, Birchall M, Song W. Recent advances in human respiratory epithelium models for drug discovery. Biotechnol Adv 2021; 54:107832. [PMID: 34481894 DOI: 10.1016/j.biotechadv.2021.107832] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/08/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022]
Abstract
The respiratory epithelium is intimately associated with the pathophysiologies of highly infectious viral contagions and chronic illnesses such as chronic obstructive pulmonary disorder, presently the third leading cause of death worldwide with a projected economic burden of £1.7 trillion by 2030. Preclinical studies of respiratory physiology have almost exclusively utilised non-humanised animal models, alongside reductionistic cell line-based models, and primary epithelial cell models cultured at an air-liquid interface (ALI). Despite their utility, these model systems have been limited by their poor correlation to the human condition. This has undermined the ability to identify novel therapeutics, evidenced by a 15% chance of success for medicinal respiratory compounds entering clinical trials in 2018. Consequently, preclinical studies require new translational efficacy models to address the problem of respiratory drug attrition. This review describes the utility of the current in vivo (rodent), ex vivo (isolated perfused lungs and precision cut lung slices), two-dimensional in vitro cell-line (A549, BEAS-2B, Calu-3) and three-dimensional in vitro ALI (gold-standard and co-culture) and organoid respiratory epithelium models. The limitations to the application of these model systems in drug discovery research are discussed, in addition to perspectives of the future innovations required to facilitate the next generation of human-relevant respiratory models.
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Affiliation(s)
- Naheem Yaqub
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Department of Surgical Biotechnology, Division of Surgery & Interventional Science, University College London, London NW3 2PF, UK
| | - Gareth Wayne
- Novel Human Genetics, GlaxoSmithKline, Stevenage SG1 2NY, UK
| | - Martin Birchall
- The Ear Institute, Faculty of Brain Sciences, University College London, London WC1X 8EE, UK.
| | - Wenhui Song
- UCL Centre for Biomaterials in Surgical Reconstruction and Regeneration, Department of Surgical Biotechnology, Division of Surgery & Interventional Science, University College London, London NW3 2PF, UK.
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37
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Pascual-Iglesias A, Canton J, Ortega-Prieto AM, Jimenez-Guardeño JM, Regla-Nava JA. An Overview of Vaccines against SARS-CoV-2 in the COVID-19 Pandemic Era. Pathogens 2021; 10:1030. [PMID: 34451494 PMCID: PMC8402174 DOI: 10.3390/pathogens10081030] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/01/2021] [Accepted: 08/11/2021] [Indexed: 12/14/2022] Open
Abstract
The emergence of SARS-CoV-2 in late 2019 led to the COVID-19 pandemic all over the world. When the virus was first isolated and its genome was sequenced in the early months of 2020, the efforts to develop a vaccine began. Based on prior well-known knowledge about coronavirus, the SARS-CoV-2 spike (S) protein was selected as the main target. Currently, more than one hundred vaccines are being investigated and several of them are already authorized by medical agencies. This review summarizes and compares the current knowledge about main approaches for vaccine development, focusing on those authorized and specifically their immunogenicity, efficacy preventing severe disease, adverse side effects, protection, and ability to cope with emergent SARS-CoV-2 variants.
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Affiliation(s)
- Alejandro Pascual-Iglesias
- The Innate Immune Response Group, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain;
- Tumor Immunology Laboratory, IdiPAZ, La Paz University Hospital, 28046 Madrid, Spain
| | - Javier Canton
- International Institute for Defense and Security (CISDE), 41007 Sevilla, Spain;
| | - Ana Maria Ortega-Prieto
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London SE1 9RT, UK;
| | - Jose M. Jimenez-Guardeño
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King’s College London, London SE1 9RT, UK;
| | - Jose Angel Regla-Nava
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
- Department of Microbiology and Pathology, University Center for Health Science (CUCS), University of Guadalajara, Guadalajara 44340, Mexico
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38
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Bioprinted Multi-Cell Type Lung Model for the Study of Viral Inhibitors. Viruses 2021; 13:v13081590. [PMID: 34452455 PMCID: PMC8402746 DOI: 10.3390/v13081590] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/05/2021] [Accepted: 08/07/2021] [Indexed: 12/13/2022] Open
Abstract
Influenza A virus (IAV) continuously causes epidemics and claims numerous lives every year. The available treatment options are insufficient and the limited pertinence of animal models for human IAV infections is hampering the development of new therapeutics. Bioprinted tissue models support studying pathogenic mechanisms and pathogen-host interactions in a human micro tissue environment. Here, we describe a human lung model, which consisted of a bioprinted base of primary human lung fibroblasts together with monocytic THP-1 cells, on top of which alveolar epithelial A549 cells were printed. Cells were embedded in a hydrogel consisting of alginate, gelatin and collagen. These constructs were kept in long-term culture for 35 days and their viability, expression of specific cell markers and general rheological parameters were analyzed. When the models were challenged with a combination of the bacterial toxins LPS and ATP, a release of the proinflammatory cytokines IL-1β and IL-8 was observed, confirming that the model can generate an immune response. In virus inhibition assays with the bioprinted lung model, the replication of a seasonal IAV strain was restricted by treatment with an antiviral agent in a dose-dependent manner. The printed lung construct provides an alveolar model to investigate pulmonary pathogenic biology and to support development of new therapeutics not only for IAV, but also for other viruses.
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Nouailles G, Wyler E, Pennitz P, Postmus D, Vladimirova D, Kazmierski J, Pott F, Dietert K, Muelleder M, Farztdinov V, Obermayer B, Wienhold SM, Andreotti S, Hoefler T, Sawitzki B, Drosten C, Sander LE, Suttorp N, Ralser M, Beule D, Gruber AD, Goffinet C, Landthaler M, Trimpert J, Witzenrath M. Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19. Nat Commun 2021; 12:4869. [PMID: 34381043 PMCID: PMC8357947 DOI: 10.1038/s41467-021-25030-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 07/13/2021] [Indexed: 01/08/2023] Open
Abstract
In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.
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Affiliation(s)
- Geraldine Nouailles
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany.
- Berlin Institute of Health (BIH), Berlin, Germany.
| | - Emanuel Wyler
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
| | - Peter Pennitz
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany
| | - Dylan Postmus
- Berlin Institute of Health (BIH), Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany
| | | | - Julia Kazmierski
- Berlin Institute of Health (BIH), Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany
| | - Fabian Pott
- Berlin Institute of Health (BIH), Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany
| | - Kristina Dietert
- Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
- Veterinary Centre for Resistance Research, Freie Universität Berlin, Berlin, Germany
| | - Michael Muelleder
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Core Facility - High-Throughput Mass Spectrometry, Berlin, Germany
| | - Vadim Farztdinov
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Core Facility - High-Throughput Mass Spectrometry, Berlin, Germany
| | - Benedikt Obermayer
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Sandra-Maria Wienhold
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany
| | - Sandro Andreotti
- Bioinformatics Solution Center, Freie Universität Berlin, Berlin, Germany
| | - Thomas Hoefler
- Institute of Virology, Freie Universität Berlin, Berlin, Germany
| | - Birgit Sawitzki
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, Berlin, Germany
| | - Christian Drosten
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany
| | - Leif E Sander
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany
| | - Norbert Suttorp
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany
| | - Markus Ralser
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London, UK
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Biochemistry, Berlin, Germany
| | - Dieter Beule
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Achim D Gruber
- Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
| | - Christine Goffinet
- Berlin Institute of Health (BIH), Berlin, Germany
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Virology, Berlin, Germany
| | - Markus Landthaler
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- IRI Life Sciences, Institute for Biology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Jakob Trimpert
- Institute of Virology, Freie Universität Berlin, Berlin, Germany.
| | - Martin Witzenrath
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Pulmonary Inflammation, Berlin, Germany.
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Infectious Diseases and Respiratory Medicine, Berlin, Germany.
- German Center for Lung Research (DZL), Berlin, Germany.
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Rudd JM, Tamil Selvan M, Cowan S, Kao YF, Midkiff CC, Narayanan S, Ramachandran A, Ritchey JW, Miller CA. Clinical and Histopathologic Features of a Feline SARS-CoV-2 Infection Model Are Analogous to Acute COVID-19 in Humans. Viruses 2021; 13:v13081550. [PMID: 34452415 PMCID: PMC8402899 DOI: 10.3390/v13081550] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 12/11/2022] Open
Abstract
The emergence and ensuing dominance of COVID-19 on the world stage has emphasized the urgency of efficient animal models for the development of therapeutics for and assessment of immune responses to SARS-CoV-2 infection. Shortcomings of current animal models for SARS-CoV-2 include limited lower respiratory disease, divergence from clinical COVID-19 disease, and requirements for host genetic modifications to permit infection. In this study, n = 12 specific-pathogen-free domestic cats were infected intratracheally with SARS-CoV-2 to evaluate clinical disease, histopathologic lesions, and viral infection kinetics at 4 and 8 days post-inoculation; n = 6 sham-inoculated cats served as controls. Intratracheal inoculation of SARS-CoV-2 produced a significant degree of clinical disease (lethargy, fever, dyspnea, and dry cough) consistent with that observed in the early exudative phase of COVID-19. Pulmonary lesions such as diffuse alveolar damage, hyaline membrane formation, fibrin deposition, and proteinaceous exudates were also observed with SARS-CoV-2 infection, replicating lesions identified in people hospitalized with ARDS from COVID-19. A significant correlation was observed between the degree of clinical disease identified in infected cats and pulmonary lesions. Viral loads and ACE2 expression were also quantified in nasal turbinates, distal trachea, lungs, and other organs. Results of this study validate a feline model for SARS-CoV-2 infection that results in clinical disease and histopathologic lesions consistent with acute COVID-19 in humans, thus encouraging its use for future translational studies.
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Affiliation(s)
- Jennifer M. Rudd
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (J.M.R.); (M.T.S.); (S.C.); (Y.-F.K.); (J.W.R.)
| | - Miruthula Tamil Selvan
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (J.M.R.); (M.T.S.); (S.C.); (Y.-F.K.); (J.W.R.)
| | - Shannon Cowan
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (J.M.R.); (M.T.S.); (S.C.); (Y.-F.K.); (J.W.R.)
| | - Yun-Fan Kao
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (J.M.R.); (M.T.S.); (S.C.); (Y.-F.K.); (J.W.R.)
| | - Cecily C. Midkiff
- Division of Comparative Pathology, Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA;
| | - Sai Narayanan
- Oklahoma Animal Disease Diagnostic Laboratory, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (S.N.); (A.R.)
| | - Akhilesh Ramachandran
- Oklahoma Animal Disease Diagnostic Laboratory, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (S.N.); (A.R.)
| | - Jerry W. Ritchey
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (J.M.R.); (M.T.S.); (S.C.); (Y.-F.K.); (J.W.R.)
| | - Craig A. Miller
- Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA; (J.M.R.); (M.T.S.); (S.C.); (Y.-F.K.); (J.W.R.)
- Correspondence:
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41
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Inde Z, Croker BA, Yapp C, Joshi GN, Spetz J, Fraser C, Qin X, Xu L, Deskin B, Ghelfi E, Webb G, Carlin AF, Zhu YP, Leibel SL, Garretson AF, Clark AE, Duran JM, Pretorius V, Crotty-Alexander LE, Li C, Lee JC, Sodhi C, Hackam DJ, Sun X, Hata AN, Kobzik L, Miller J, Park JA, Brownfield D, Jia H, Sarosiek KA. Age-dependent regulation of SARS-CoV-2 cell entry genes and cell death programs correlates with COVID-19 severity. SCIENCE ADVANCES 2021; 7:eabf8609. [PMID: 34407940 PMCID: PMC8373124 DOI: 10.1126/sciadv.abf8609] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 06/25/2021] [Indexed: 05/02/2023]
Abstract
Novel coronavirus disease 2019 (COVID-19) severity is highly variable, with pediatric patients typically experiencing less severe infection than adults and especially the elderly. The basis for this difference is unclear. We find that mRNA and protein expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19, increases with advancing age in distal lung epithelial cells. However, in humans, ACE2 expression exhibits high levels of intra- and interindividual heterogeneity. Further, cells infected with SARS-CoV-2 experience endoplasmic reticulum stress, triggering an unfolded protein response and caspase-mediated apoptosis, a natural host defense system that halts virion production. Apoptosis of infected cells can be selectively induced by treatment with apoptosis-modulating BH3 mimetic drugs. Notably, epithelial cells within young lungs and airways are more primed to undergo apoptosis than those in adults, which may naturally hinder virion production and support milder COVID-19 severity.
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Affiliation(s)
- Zintis Inde
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
| | - Ben A Croker
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Clarence Yapp
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
- Image and Data Analysis Core, Harvard Medical School, Boston, MA, USA
| | - Gaurav N Joshi
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
- Integrated Cellular Imaging Core, Emory University, Atlanta, GA, USA
| | - Johan Spetz
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
| | - Cameron Fraser
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
| | - Xingping Qin
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
| | - Le Xu
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Brian Deskin
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Elisa Ghelfi
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Gabrielle Webb
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Aaron F Carlin
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Yanfang Peipei Zhu
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Sandra L Leibel
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA
| | - Aaron F Garretson
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Alex E Clark
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jason M Duran
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Victor Pretorius
- Department of Surgery, University of California San Diego, La Jolla, CA, USA
| | | | - Chendi Li
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jamie Casey Lee
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Chhinder Sodhi
- Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
| | - David J Hackam
- Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
| | - Xin Sun
- Department of Pediatrics, University of California San Diego, La Jolla, CA, USA
| | - Aaron N Hata
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Lester Kobzik
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jeffrey Miller
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jin-Ah Park
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Douglas Brownfield
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Hongpeng Jia
- Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
| | - Kristopher A Sarosiek
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA
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42
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Pandey K, Acharya A, Mohan M, Ng CL, Reid SP, Byrareddy SN. Animal models for SARS-CoV-2 research: A comprehensive literature review. Transbound Emerg Dis 2021; 68:1868-1885. [PMID: 33128861 PMCID: PMC8085186 DOI: 10.1111/tbed.13907] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 10/09/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022]
Abstract
Emerging and re-emerging viral diseases can create devastating effects on human lives and may also lead to economic crises. The ongoing COVID-19 pandemic due to the novel coronavirus (nCoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, has caused a global public health emergency. To date, the molecular mechanism of transmission of SARS-CoV-2, its clinical manifestations and pathogenesis is not completely understood. The global scientific community has intensified its efforts in understanding the biology of SARS-CoV-2 for development of vaccines and therapeutic interventions to prevent the rapid spread of the virus and to control mortality and morbidity associated with COVID-19. To understand the pathophysiology of SARS-CoV-2, appropriate animal models that mimic the biology of human SARS-CoV-2 infection are urgently needed. In this review, we outline animal models that have been used to study previous human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). Importantly, we discuss models that are appropriate for SARS-CoV-2 as well as the advantages and disadvantages of various available methods.
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Affiliation(s)
- Kabita Pandey
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mahesh Mohan
- Texas Biomedical Research Institute, Southwest National Primate Research Center, San Antonio, TX, USA
| | - Caroline L Ng
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - St Patrick Reid
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Centre, Omaha, NE, USA
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Centre, Omaha, NE, USA
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43
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Babadaei MMN, Hasan A, Vahdani Y, Bloukh SH, Sharifi M, Kachooei E, Haghighat S, Falahati M. Development of remdesivir repositioning as a nucleotide analog against COVID-19 RNA dependent RNA polymerase. J Biomol Struct Dyn 2021; 39:3771-3779. [PMID: 32397906 PMCID: PMC7256352 DOI: 10.1080/07391102.2020.1767210] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 05/06/2020] [Indexed: 12/15/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative representative of a severe respiratory illness resulted in widespread human infections and deaths in nearly all of the countries since late 2019. There is no therapeutic FDA-approved drug against SARS-CoV-2 infection, although a combination of anti-viral drugs is directly being practiced in some countries. A broad-spectrum of antiviral agents are being currently evaluated in clinical trials, and in this review, we specifically focus on the application of Remdesivir (RVD) as a potential anti-viral compound against Middle East respiratory syndrome (MERS) -CoV, SARS-CoV and SARS-CoV-2. First, we overview the general information about SARS-CoV-2, followed by application of RDV as a nucleotide analogue which can potentially inhibits RNA-dependent RNA polymerase of COVs. Afterwards, we discussed the kinetics of SARS- or MERS-CoV proliferation in animal models which is significantly different compared to that in humans. Finally, some ongoing challenges and future perspective on the application of RDV either alone or in combination with other anti-viral agents against CoVs infection were surveyed to determine the efficiency of RDV in preclinical trials. As a result, this paper provides crucial evidence of the potency of RDV to prevent SARS-CoV-2 infections.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Mohammad Mahdi Nejadi Babadaei
- Department of Molecular Genetics, Faculty of Biological Science, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Anwarul Hasan
- Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar
- Biomedical Research Center, Qatar University, Doha, Qatar
| | - Yasaman Vahdani
- Department of Microbiology, Faculty of Pharmaceutical Sciences, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Samir Haj Bloukh
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Majid Sharifi
- Department of Nanotechnology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ehsan Kachooei
- Department of Molecular Sciences, Macquarie University, Sydney, Australia
| | - Setareh Haghighat
- Department of Microbiology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mojtaba Falahati
- Department of Nanotechnology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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44
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Lemaitre J, Naninck T, Delache B, Creppy J, Huber P, Holzapfel M, Bouillier C, Contreras V, Martinon F, Kahlaoui N, Pascal Q, Tricot S, Ducancel F, Vecellio L, Le Grand R, Maisonnasse P. Non-human primate models of human respiratory infections. Mol Immunol 2021; 135:147-164. [PMID: 33895579 PMCID: PMC8062575 DOI: 10.1016/j.molimm.2021.04.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/03/2021] [Accepted: 04/12/2021] [Indexed: 12/25/2022]
Abstract
Respiratory pathogens represent a great burden for humanity and a potential source of new pandemics, as illustrated by the recent emergence of coronavirus disease 2019 (COVID-19). In recent decades, biotechnological advances have led to the development of numerous innovative therapeutic molecules and vaccine immunogens. However, we still lack effective treatments and vaccines against many respiratory pathogens. More than ever, there is a need for a fast, predictive, preclinical pipeline, to keep pace with emerging diseases. Animal models are key for the preclinical development of disease management strategies. The predictive value of these models depends on their ability to reproduce the features of the human disease, the mode of transmission of the infectious agent and the availability of technologies for monitoring infection. This review focuses on the use of non-human primates as relevant preclinical models for the development of prevention and treatment for human respiratory infections.
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Affiliation(s)
- Julien Lemaitre
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Thibaut Naninck
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Benoît Delache
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Justina Creppy
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France; Centre d'Etude des Pathologies Respiratoires, INSERM U1100, Université de Tours, Tours, France
| | - Philippe Huber
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Marion Holzapfel
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Camille Bouillier
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Vanessa Contreras
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Frédéric Martinon
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Nidhal Kahlaoui
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Quentin Pascal
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Sabine Tricot
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Frédéric Ducancel
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Laurent Vecellio
- Centre d'Etude des Pathologies Respiratoires, INSERM U1100, Université de Tours, Tours, France; Plateforme Scientifique et Technique Animaleries (PST-A), Université de Tours, Tours, France
| | - Roger Le Grand
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France
| | - Pauline Maisonnasse
- Université Paris-Saclay, INSERM, CEA, Center for Immunology of Viral, Autoimmune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses & Le Kremlin-Bicêtre, France.
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45
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Younes S, Younes N, Shurrab F, Nasrallah GK. Severe acute respiratory syndrome coronavirus-2 natural animal reservoirs and experimental models: systematic review. Rev Med Virol 2021; 31:e2196. [PMID: 33206434 PMCID: PMC7744864 DOI: 10.1002/rmv.2196] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/30/2020] [Accepted: 11/02/2020] [Indexed: 12/14/2022]
Abstract
The current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak has been rapidly spreading worldwide, causing serious global concern. The role that animal hosts play in disease transmission is still understudied and researchers wish to find suitable animal models for fundamental research and drug discovery. In this systematic review, we aimed to compile and discuss all articles that describe experimental or natural infections with SARS-CoV-2, from the initial discovery of the virus in December 2019 through to October 2020. We systematically searched four databases (Scopus, PubMed, Science Direct and Web of Science). The following data were extracted from the included studies: type of infection (natural or experimental), age, sample numbers, dose, route of inoculation, viral replication, detection method, clinical symptoms and transmission. Fifty-four studies were included, of which 34 were conducted on animal reservoirs (naturally or experimentally infected), and 20 involved models for testing vaccines and therapeutics. Our search revealed that Rousettus aegyptiacus (fruit bats), pangolins, felines, mink, ferrets and rabbits were all susceptible to SARS-CoV-2, while dogs were weakly susceptible and pigs, poultry, and tree shrews were not. In addition, virus replication in mice, mink, hamsters and ferrets resembled subclinical human infection, so these animals might serve as useful models for future studies to evaluate vaccines or antiviral agents and to study host-pathogen interactions. Our review comprehensively summarized current evidence on SARS-CoV-2 infection in animals and their usefulness as models for studying vaccines and antiviral drugs. Our findings may direct future studies for vaccine development, antiviral drugs and therapeutic agents to manage SARS-CoV-2-caused diseases.
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Affiliation(s)
- Salma Younes
- Biomedical Research CenterMember of QU HealthQatar UniversityDohaQatar
| | - Nadin Younes
- Biomedical Research CenterMember of QU HealthQatar UniversityDohaQatar
| | - Farah Shurrab
- Biomedical Research CenterMember of QU HealthQatar UniversityDohaQatar
| | - Gheyath K. Nasrallah
- Biomedical Research CenterMember of QU HealthQatar UniversityDohaQatar
- Department of Biomedical ScienceCollege of Health SciencesMember of QU HealthQatar UniversityDohaQatar
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Shirbhate E, Patel P, Patel VK, Veerasamy R, Sharma PC, Sinha BN, Rajak H. Synthetic and Semi-synthetic Drugs as a Promising Therapeutic Option for the Treatment of COVID-19. Mini Rev Med Chem 2021; 21:1004-1016. [PMID: 33280595 DOI: 10.2174/1389557520666201204162103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/23/2020] [Accepted: 10/16/2020] [Indexed: 11/22/2022]
Abstract
The novel coronavirus disease-19 (COVID-19) is a global pandemic that emerged from Wuhan, China, and has spread all around the world, affecting 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 updates of August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine exists. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID- 19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in clinical uses or studies on COVID-19 and also focuses on the mode of action of drugs being repositioned against COVID-19.
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Affiliation(s)
- Ekta Shirbhate
- Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495 009, C.G., India
| | - Preeti Patel
- Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495 009, C.G., India
| | - Vijay K Patel
- Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495 009, C.G., India
| | - Ravichandran Veerasamy
- Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia
| | - Prabodh C Sharma
- Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136 119, Haryana, India
| | - Barij N Sinha
- Department of Pharmacy, Birla Institute of Technology, Mesra - Ranchi-835 215, Jharkhand, India
| | - Harish Rajak
- Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur 495 009, C.G., India
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Goyal A, Reeves DB, Thakkar N, Famulare M, Cardozo-Ojeda EF, Mayer BT, Schiffer JT. Slight reduction in SARS-CoV-2 exposure viral load due to masking results in a significant reduction in transmission with widespread implementation. Sci Rep 2021; 11:11838. [PMID: 34088959 PMCID: PMC8178300 DOI: 10.1038/s41598-021-91338-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 05/12/2021] [Indexed: 12/19/2022] Open
Abstract
Masks are a vital tool for limiting SARS-CoV-2 spread in the population. Here we utilize a mathematical model to assess the impact of masking on transmission within individual transmission pairs and at the population level. Our model quantitatively links mask efficacy to reductions in viral load and subsequent transmission risk. Our results reinforce that the use of masks by both a potential transmitter and exposed person substantially reduces the probability of successful transmission, even if masks only lower exposure viral load by ~ 50%. Slight increases in mask adherence and/or efficacy above current levels would reduce the effective reproductive number (Re) substantially below 1, particularly if implemented comprehensively in potential super-spreader environments. Our model predicts that moderately efficacious masks will also lower exposure viral load tenfold among people who get infected despite masking, potentially limiting infection severity. Because peak viral load tends to occur pre-symptomatically, we also identify that antiviral therapy targeting symptomatic individuals is unlikely to impact transmission risk. Instead, antiviral therapy would only lower Re if dosed as post-exposure prophylaxis and if given to ~ 50% of newly infected people within 3 days of an exposure. These results highlight the primacy of masking relative to other biomedical interventions under consideration for limiting the extent of the COVID-19 pandemic prior to widespread implementation of a vaccine. To confirm this prediction, we used a regression model of King County, Washington data and simulated the counterfactual scenario without mask wearing to estimate that in the absence of additional interventions, mask wearing decreased Re from 1.3-1.5 to ~ 1.0 between June and September 2020.
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Affiliation(s)
- Ashish Goyal
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA
| | - Daniel B Reeves
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA
| | - Niket Thakkar
- Institute for Disease Modeling, Global Health Division, Bill and Melinda Gates Foundation, Seattle, USA
| | - Mike Famulare
- Institute for Disease Modeling, Global Health Division, Bill and Melinda Gates Foundation, Seattle, USA
| | - E Fabián Cardozo-Ojeda
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA
| | - Bryan T Mayer
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA
| | - Joshua T Schiffer
- Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
- Department of Medicine, University of Washington, Seattle, USA.
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
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48
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Kumar S, Sarma P, Kaur H, Prajapat M, Bhattacharyya A, Avti P, Sehkhar N, Kaur H, Bansal S, Mahendiratta S, Mahalmani VM, Singh H, Prakash A, Kuhad A, Medhi B. Clinically relevant cell culture models and their significance in isolation, pathogenesis, vaccine development, repurposing and screening of new drugs for SARS-CoV-2: a systematic review. Tissue Cell 2021; 70:101497. [PMID: 33550034 PMCID: PMC7836970 DOI: 10.1016/j.tice.2021.101497] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 01/17/2021] [Accepted: 01/17/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND In-Vitro/Cellular evidence is the backbone and vital proof of concept during the development of novel therapeutics as well as drugs repurposing against COVID-19. Choosing an ideal in-vitro model is vital as the virus entry is through ACE2, CD147, and TMPRSS2 dependant and very specific. In this regard, this is the first systematic review addressing the importance of specific cell lines used as potential in-vitro models in the isolation, pathogenesis, and therapeutics for SARS-COV-2. METHODS We searched 17 literature databases with appropriate keywords, and identified 1173 non-duplicate studies. In the present study, 71 articles are included after a careful, thorough screening of the titles and their abstracts for possible inclusion using predefined inclusion/exclusion criteria (PRISMA Guidelines). RESULTS In the current study, we compiled cell culture-based studies for SARS-CoV-2 and found the best compatible In-Vitro models for SARS-CoV-2 (Vero, VeroE6, HEK293 as well as its variants, Huh-7, Calu-3 2B4, and Caco2). Among other essential cell lines used include LLC-MK2, MDCKII, BHK-21, HepG2, A549,T cell leukemia (MT-2), stems cells based cell line DYR0100for differentiation assays, and embryo-specific NIH3T3 cell line for vaccine production. CONCLUSION The Present study provides a detailed summary of all the drugs/compounds screened for drug repurposing and discovery purpose using the in-vitro models for SARS-CoV-2 along with isolation, pathogenesis and vaccine production. This study also suggests that after careful evaluation of all the cell line based studies, Kidney cells (VeroE6, HEK293 along with their clones), liver Huh-7cells, respiratory Calu-3 cells, and intestinal Caco-2 are the most widely used in-vitro models for SARS-CoV-2.
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Affiliation(s)
- Subodh Kumar
- Department of Pharmacology, PGIMER, Chandigarh, India.
| | - Phulen Sarma
- Department of Pharmacology, PGIMER, Chandigarh, India.
| | - Hardeep Kaur
- Department of Pharmacology, PGIMER, Chandigarh, India.
| | | | | | - Pramod Avti
- Department of Biophysics, PGIMER, Chandigarh, India.
| | | | | | - Seema Bansal
- Department of Pharmacology, PGIMER, Chandigarh, India.
| | | | | | | | - Ajay Prakash
- Department of Pharmacology, PGIMER, Chandigarh, India.
| | - Anurag Kuhad
- University Institute of Pharmaceutical Sciences (UIPS). Panjab University, Chandigarh, India.
| | - Bikash Medhi
- Department of Pharmacology, PGIMER, Chandigarh, India.
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de Dios-Figueroa GT, Aguilera-Marquez JDR, Camacho-Villegas TA, Lugo-Fabres PH. 3D Cell Culture Models in COVID-19 Times: A Review of 3D Technologies to Understand and Accelerate Therapeutic Drug Discovery. Biomedicines 2021; 9:602. [PMID: 34073231 PMCID: PMC8226796 DOI: 10.3390/biomedicines9060602] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/15/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
In the last decades, emerging viruses have become a worldwide concern. The fast and extensive spread of the disease caused by SARS-CoV-2 (COVID-19) has impacted the economy and human activity worldwide, highlighting the human vulnerability to infectious diseases and the need to develop and optimize technologies to tackle them. The three-dimensional (3D) cell culture models emulate major tissue characteristics such as the in vivo virus-host interactions. These systems may help to generate a quick response to confront new viruses, establish a reliable evaluation of the pathophysiology, and contribute to therapeutic drug evaluation in pandemic situations such as the one that humanity is living through today. This review describes different types of 3D cell culture models, such as spheroids, scaffolds, organoids, and organs-on-a-chip, that are used in virus research, including those used to understand the new severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2).
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Affiliation(s)
- Guadalupe Tonantzin de Dios-Figueroa
- Department of Medical and Pharmaceutical Biotechnology, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C. (CIATEJ), Av. Normalistas 800, Colinas de las Normal, Guadalajara, Jalisco 44270, Mexico; (G.T.d.D.-F.); (J.d.R.A.-M.)
| | - Janette del Rocío Aguilera-Marquez
- Department of Medical and Pharmaceutical Biotechnology, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C. (CIATEJ), Av. Normalistas 800, Colinas de las Normal, Guadalajara, Jalisco 44270, Mexico; (G.T.d.D.-F.); (J.d.R.A.-M.)
| | - Tanya A. Camacho-Villegas
- CONACYT-Department of Medical and Pharmaceutical Biotechnology, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C. (CIATEJ), Av. Normalistas 800, Colinas de las Normal, Guadalajara, Jalisco 44270, Mexico;
| | - Pavel H. Lugo-Fabres
- CONACYT-Department of Medical and Pharmaceutical Biotechnology, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco A.C. (CIATEJ), Av. Normalistas 800, Colinas de las Normal, Guadalajara, Jalisco 44270, Mexico;
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50
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Koch T, Fathi A, Addo MM. The COVID-19 Vaccine Landscape. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1318:549-573. [PMID: 33973199 DOI: 10.1007/978-3-030-63761-3_31] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The history of vaccine development spans centuries. At first, whole pathogens were used as vaccine agents, either inactivated or attenuated, to reduce virulence in humans. Safety and tolerability were increased by including only specific proteins as antigens and using cell culture methods, while novel vaccine strategies, like nucleic acid- or vector-based vaccines, hold high promise for the future. Vaccines have generally not been employed as the primary tools in outbreak response, but this might change since advances in medical technology in the last decades have made the concept of developing vaccines against novel pathogens a realistic strategy. Wandering the uncharted territory of a novel pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we can learn from other human Betacoronaviridae that emerged in the last decades, SARS-CoV-1 and MERS-CoV. We can identify the most likely target structures of immunity, establish animal models that emulate human disease and immunity as closely as possible, and learn about complex mechanisms of immune interaction such as cross-reactivity or antibody-dependent enhancement (ADE). However, significant knowledge gaps remain. What are the correlates of protection? How do we best induce immunity in vulnerable populations like the elderly? Will the immunity induced by vaccination (or by natural infection) wane over time? To date, at least 149 vaccine candidates against SARS-CoV-2 are under development. At the time of writing, at least 17 candidates have already progressed past preclinical studies (in vitro models and in vivo animal experiments) into clinical development. This chapter will provide an overview of this rapidly developing field.
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Affiliation(s)
- Till Koch
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. .,Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. .,German Center for Infection Research, Hamburg-Lubeck-Borstel-Riems, Hamburg, Germany.
| | - Anahita Fathi
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research, Hamburg-Lubeck-Borstel-Riems, Hamburg, Germany
| | - Marylyn M Addo
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research, Hamburg-Lubeck-Borstel-Riems, Hamburg, Germany
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