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Du Y, Gao J, He M, Yi M, Wu J, Feng L, Zeng B, Li Y, He R, Wang Y, Qin CF, Cui Z, Wang C. Simultaneous Blockade of CD209 and CD209L by Monoclonal Antibody Does Not Provide Sufficient Protection Against Multiple Viral Infections In Vivo. Immunology 2025; 174:411-422. [PMID: 39783143 DOI: 10.1111/imm.13889] [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: 09/19/2024] [Revised: 11/18/2024] [Accepted: 12/10/2024] [Indexed: 01/12/2025] Open
Abstract
Many virus species, including Ebola virus, Marburg virus, SARS-CoV-2, dengue virus (DENV) and Zika virus (ZIKV), exploit CD209 and CD209L as alternative or attachment receptors for viral cis- or trans-infection. Thus, CD209 and CD209L may be critical targets for the development of therapeutic monoclonal blocking antibody drugs to disrupt the infection process caused by multiple viruses. Here, we produced a human chimeric monoclonal blocking antibody that simultaneously blocks CD209 and CD209L, namely 7-H7-B1. We show that 7-H7-B1 effectively blocks multiple pseudotyped or live viral infections in vitro, including SARS-CoV, SARS-CoV-2, Ebola virus, Marburg virus, ZIKV and DENV infections. However, the 7-H7-B1 mAb does not provide favourable protection against Zaire Ebola virus or ZIKV infection in hCD209 knock-in mice in vivo. Thus, our findings indicate that although CD209 and CD209L are critical for multiple viral infections in vitro, they may play only a partial role in viral infections in vivo.
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MESH Headings
- Animals
- Humans
- Mice
- Cell Adhesion Molecules/immunology
- Cell Adhesion Molecules/antagonists & inhibitors
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/immunology
- Receptors, Cell Surface/immunology
- Receptors, Cell Surface/antagonists & inhibitors
- Lectins, C-Type/immunology
- Lectins, C-Type/antagonists & inhibitors
- Zika Virus/immunology
- SARS-CoV-2/immunology
- Ebolavirus/immunology
- Zika Virus Infection/immunology
- Antibodies, Blocking/pharmacology
- Antibodies, Blocking/immunology
- Dengue Virus
- Vero Cells
- Virus Diseases/immunology
- Receptors, Virus/antagonists & inhibitors
- Receptors, Virus/immunology
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Affiliation(s)
- Yanyun Du
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jiawang Gao
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P.R. China
- University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Mengjiao He
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, China
- Research Unit of Discovery and Tracing of Natural Focus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Yi
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jiaqi Wu
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Lingyun Feng
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Bo Zeng
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yangyang Li
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ruirui He
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yuan Wang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Cheng-Feng Qin
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences (AMMS), Beijing, China
- Research Unit of Discovery and Tracing of Natural Focus Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Zongqiang Cui
- State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, P.R. China
- University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Chenhui Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province, Department of Laboratory Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Sichuan Medical Laboratory Clinical Medical Research Center, Sichuan Provincial People's Hospital, Chengdu, China
- Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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de Oliveira Silva Pinto M, de Paula Pereira L, de Mendonça Angelo ALP, Xavier MAP, de Magalhães Vieira Machado A, Russo RC. Dissecting the COVID-19 Immune Response: Unraveling the Pathways of Innate Sensing and Response to SARS-CoV-2 Structural Proteins. J Mol Recognit 2025; 38:e70002. [PMID: 39905998 DOI: 10.1002/jmr.70002] [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: 11/08/2024] [Revised: 01/15/2025] [Accepted: 01/22/2025] [Indexed: 02/06/2025]
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV), the virus responsible for COVID-19, interacts with the host immune system through complex mechanisms that significantly influence disease outcomes, affecting both innate and adaptive immunity. These interactions are crucial in determining the disease's severity and the host's ability to clear the virus. Given the virus's substantial socioeconomic impact, high morbidity and mortality rates, and public health importance, understanding these mechanisms is essential. This article examines the diverse innate immune responses triggered by SARS-CoV-2's structural proteins, including the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins, along with nonstructural proteins (NSPs) and open reading frames. These proteins play pivotal roles in immune modulation, facilitating viral replication, evading immune detection, and contributing to severe inflammatory responses such as cytokine storms and acute respiratory distress syndrome (ARDS). The virus employs strategies like suppressing type I interferon production and disrupting key antiviral pathways, including MAVS, OAS-RNase-L, and PKR. This study also explores the immune pathways that govern the activation and suppression of immune responses throughout COVID-19. By analyzing immune sensing receptors and the responses initiated upon recognizing SARS-CoV-2 structural proteins, this review elucidates the complex pathways associated with the innate immune response in COVID-19. Understanding these mechanisms offers valuable insights for therapeutic interventions and informs public health strategies, contributing to a deeper understanding of COVID-19 immunopathogenesis.
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Affiliation(s)
- Matheus de Oliveira Silva Pinto
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
- Viral Disease Immunology Group, Fundação Osvaldo Cruz, Instituto René Rachou, Belo Horizonte, Minas Gerais, Brazil
| | - Leonardo de Paula Pereira
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
- Viral Disease Immunology Group, Fundação Osvaldo Cruz, Instituto René Rachou, Belo Horizonte, Minas Gerais, Brazil
| | | | | | | | - Remo Castro Russo
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
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Liu KS, Wang L, Chen PM, Lee IK, Yang KD, Chen RF. MCP-1 Reduction by L-SIGN Expression in Dengue Virus-Infected Liver Endothelial Cells. Viruses 2025; 17:344. [PMID: 40143272 PMCID: PMC11945572 DOI: 10.3390/v17030344] [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: 11/11/2024] [Revised: 02/24/2025] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
(1) Background: The C-type lectin domain family 4 member M (CLEC4M, also known as L-SIGN) is a crucial pathogen-recognition receptor for the dengue virus (DENV). Our previous study has exhibited a polymorphism in its extracellular neck region, specifically within the long tandem repeats of exon 4, which correlates with DHF in DENV infection and causes liver damage. (2) Methods: Using monocyte-derived dendritic cells (MDDCs) and SK-HEP1 liver endothelial cell lines to compare viral replication relative to L-SIGN expression. (3) Results: Results indicated that SK-HEP1 cells were more susceptible to DENV infection than MDDCs, and L-SIGN transfection significantly increased viral replication in SK-HEP1 cell lines. The study also found that L-SIGN-enhanced DENV infection is mediated by the decrease in monocyte chemoattractant protein-1 (MCP-1) but not interferon gamma inducible protein-10 (IP-10). These findings reveal that L-SIGN-induced DENV infection leads to reduced MCP-1 levels, which, in turn, enhances DENV replication velocity. (4) Conclusions: This study offers insights into the molecular mechanisms of DENV replication and identifies potential therapeutic targets involving MCP-1 and L-SIGN pathways.
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Affiliation(s)
- Keh-Sen Liu
- Division of Infectious Diseases, Department of Internal Medicine, Show Chwan Memorial Hospital, Changhua 500, Taiwan;
| | - Lin Wang
- Department of Pediatrics, Pojen Hospital, Kaohsiung 807, Taiwan
| | - Po-Ming Chen
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua 500, Taiwan;
- Department of Nursing, Central Taiwan University of Science and Technology, Taichung 406, Taiwan
| | - Ing-Kit Lee
- Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Medical Center, Kaohsiung 803, Taiwan
| | - Kuender D. Yang
- Department of Medical Research, MacKay Memorial Hospital, Taipei 104, Taiwan
- Department of Pediatrics, MacKay Memorial Hospital, Taipei 104, Taiwan
- Department of Medicine, MacKay Medical College, New Taipei 252, Taiwan
| | - Rong-Fu Chen
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Subramaniam S, Jose A, Kenney D, O’Connell AK, Bosmann M, Douam F, Crossland N. Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence. Front Immunol 2025; 16:1443932. [PMID: 39967675 PMCID: PMC11832389 DOI: 10.3389/fimmu.2025.1443932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 01/14/2025] [Indexed: 02/20/2025] Open
Affiliation(s)
- Saravanan Subramaniam
- Department of Pharmacology and Toxicology, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, United States
- Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Asha Jose
- Renal Section, Department of Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Devin Kenney
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Aoife K. O’Connell
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Markus Bosmann
- Department of Medicine, Pulmonary Center, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
- Department of Pathology and Laboratory Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
| | - Florian Douam
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
| | - Nicholas Crossland
- Department of Virology, Immunology and Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, United States
- National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, Boston, MA, United States
- Department of Pathology and Laboratory Medicine, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, United States
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Delaunay C, Pollastri S, Thépaut M, Cavazzoli G, Belvisi L, Bouchikri C, Labiod N, Lasala F, Gimeno A, Franconetti A, Jiménez-Barbero J, Ardá A, Delgado R, Bernardi A, Fieschi F. Unprecedented selectivity for homologous lectin targets: differential targeting of the viral receptors L-SIGN and DC-SIGN. Chem Sci 2024:d4sc02980a. [PMID: 39246372 PMCID: PMC11376147 DOI: 10.1039/d4sc02980a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/13/2024] [Indexed: 09/10/2024] Open
Abstract
DC-SIGN (CD209) and L-SIGN (CD209L) are two C-type lectin receptors (CLRs) that facilitate SARS-CoV-2 infections as viral co-receptors. SARS-CoV-2 manipulates both DC-SIGN and L-SIGN for enhanced infection, leading to interest in developing receptor antagonists. Despite their structural similarity (82% sequence identity), they function differently. DC-SIGN, found in dendritic cells, shapes the immune response by recognizing pathogen-associated carbohydrate patterns. In contrast, L-SIGN, expressed in airway epithelial endothelial cells, is not directly involved in immunity. COVID-19's primary threat is the hyperactivation of the immune system, potentially reinforced if DC-SIGN engages with exogenous ligands. Therefore, L-SIGN, co-localized with ACE2-expressing cells in the respiratory tract, is a more suitable target for anti-adhesion therapy. However, designing a selective ligand for L-SIGN is challenging due to the high sequence identity of the Carbohydrate Recognition Domains (CRDs) of the two lectins. We here present Man84, a mannose ring modified with a methylene guanidine triazole at position 2. It binds L-SIGN with a K D of 12.7μM ± 1 μM (ITC) and is the first known L-SIGN selective ligand, showing 50-fold selectivity over DC-SIGN (SPR). The X-ray structure of the L-SIGN CRD/Man84 complex reveals the guanidinium group's role in achieving steric and electrostatic complementarity with L-SIGN. This allows us to trace the source of selectivity to a single amino acid difference between the two CRDs. NMR analysis confirms the binding mode in solution, highlighting Man84's conformational selection upon complex formation. Dimeric versions of Man84 achieve additional selectivity and avidity in the low nanomolar range. These compounds selectively inhibit L-SIGN dependent trans-infection by SARS-CoV-2 and Ebola virus. Man84 and its dimeric constructs display the best affinity and avidity reported to date for low-valency glycomimetics targeting CLRs. They are promising tools for competing with SARS-CoV-2 anchoring in the respiratory tract and have potential for other medical applications.
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Affiliation(s)
- Clara Delaunay
- Université Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale Grenoble France
| | - Sara Pollastri
- Università degli Studi di Milano, Dipartimento di Chimica via Golgi 19 Milano Italy
| | - Michel Thépaut
- Université Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale Grenoble France
| | - Gianluca Cavazzoli
- Università degli Studi di Milano, Dipartimento di Chimica via Golgi 19 Milano Italy
| | - Laura Belvisi
- Università degli Studi di Milano, Dipartimento di Chimica via Golgi 19 Milano Italy
| | - Clémentine Bouchikri
- Université Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale Grenoble France
| | - Nuria Labiod
- Instituto de Investigacion Hospital Universitario 12 de Octubre, Universidad Complutense, School of Medicine Madrid Spain
| | - Fatima Lasala
- Instituto de Investigacion Hospital Universitario 12 de Octubre, Universidad Complutense, School of Medicine Madrid Spain
| | - Ana Gimeno
- Chemical Glycobiology Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) 48160 Derio Bizkaia Spain
| | - Antonio Franconetti
- Chemical Glycobiology Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) 48160 Derio Bizkaia Spain
| | - Jesús Jiménez-Barbero
- Chemical Glycobiology Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) 48160 Derio Bizkaia Spain
- Ikerbasque, Basque Foundation for Science Bilbao Spain
- Centro de Investigacion Biomedica En Red de Enfermedades Respiratorias 28029 Madrid Spain
| | - Ana Ardá
- Chemical Glycobiology Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA) 48160 Derio Bizkaia Spain
- Ikerbasque, Basque Foundation for Science Bilbao Spain
| | - Rafael Delgado
- Instituto de Investigacion Hospital Universitario 12 de Octubre, Universidad Complutense, School of Medicine Madrid Spain
- School of Medicine, Universidad Complutense Madrid Spain
| | - Anna Bernardi
- Università degli Studi di Milano, Dipartimento di Chimica via Golgi 19 Milano Italy
| | - Franck Fieschi
- Université Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale Grenoble France
- Institut Universitaire de France (IUF) Paris France
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Shouman S, El-Kholy N, Hussien AE, El-Derby AM, Magdy S, Abou-Shanab AM, Elmehrath AO, Abdelwaly A, Helal M, El-Badri N. SARS-CoV-2-associated lymphopenia: possible mechanisms and the role of CD147. Cell Commun Signal 2024; 22:349. [PMID: 38965547 PMCID: PMC11223399 DOI: 10.1186/s12964-024-01718-3] [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: 02/24/2024] [Accepted: 06/15/2024] [Indexed: 07/06/2024] Open
Abstract
T lymphocytes play a primary role in the adaptive antiviral immunity. Both lymphocytosis and lymphopenia were found to be associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While lymphocytosis indicates an active anti-viral response, lymphopenia is a sign of poor prognosis. T-cells, in essence, rarely express ACE2 receptors, making the cause of cell depletion enigmatic. Moreover, emerging strains posed an immunological challenge, potentially alarming for the next pandemic. Herein, we review how possible indirect and direct key mechanisms could contribute to SARS-CoV-2-associated-lymphopenia. The fundamental mechanism is the inflammatory cytokine storm elicited by viral infection, which alters the host cell metabolism into a more acidic state. This "hyperlactic acidemia" together with the cytokine storm suppresses T-cell proliferation and triggers intrinsic/extrinsic apoptosis. SARS-CoV-2 infection also results in a shift from steady-state hematopoiesis to stress hematopoiesis. Even with low ACE2 expression, the presence of cholesterol-rich lipid rafts on activated T-cells may enhance viral entry and syncytia formation. Finally, direct viral infection of lymphocytes may indicate the participation of other receptors or auxiliary proteins on T-cells, that can work alone or in concert with other mechanisms. Therefore, we address the role of CD147-a novel route-for SARS-CoV-2 and its new variants. CD147 is not only expressed on T-cells, but it also interacts with other co-partners to orchestrate various biological processes. Given these features, CD147 is an appealing candidate for viral pathogenicity. Understanding the molecular and cellular mechanisms behind SARS-CoV-2-associated-lymphopenia will aid in the discovery of potential therapeutic targets to improve the resilience of our immune system against this rapidly evolving virus.
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Affiliation(s)
- Shaimaa Shouman
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Nada El-Kholy
- Department of Drug Discovery, H. Lee Moffit Cancer Center& Research Institute, Tampa, FL, 33612, USA
- Cancer Chemical Biology Ph.D. Program, University of South Florida, Tampa, FL, 33620, USA
| | - Alaa E Hussien
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Azza M El-Derby
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Shireen Magdy
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | - Ahmed M Abou-Shanab
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
| | | | - Ahmad Abdelwaly
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
- Institute for Computational Molecular Science, Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA
| | - Mohamed Helal
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt
- Medicinal Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine, Zewail City of Science and Technology, Giza, 12587, Egypt.
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12587, Egypt.
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7
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Yang Y, Jeong J, Su T, Lai S, Zhang P, Garcia-Milian R, Graham M, Liu X, McConnell MJ, Utsumi T, Pereira J, Iwakiri Y. Interleukin-7-based identification of liver lymphatic endothelial cells reveals their unique structural features. JHEP Rep 2024; 6:101069. [PMID: 38966234 PMCID: PMC11222939 DOI: 10.1016/j.jhepr.2024.101069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 03/01/2024] [Accepted: 03/11/2024] [Indexed: 07/06/2024] Open
Abstract
Background & Aims The lymphatic system plays crucial roles in maintaining fluid balance and immune regulation. Studying the liver lymphatics has been considered challenging, as common lymphatic endothelial cell (LyEC) markers are expressed by other liver cells. Additionally, isolation of sufficient numbers of LyECs has been challenging because of their extremely low abundance (<0.01% of entire liver cell population) in a normal liver. Methods Potential LyEC markers was identified using our published single-cell RNA sequencing (scRNA-seq) dataset (GSE147581) in mouse livers. Interleukin-7 (IL7) promoter-driven green fluorescent protein knock-in heterozygous mice were used for the validation of IL7 expression in LyECs in the liver, for the development of liver LyEC isolation protocol, and generating liver ischemia/reperfusion (I/R) injury. Scanning electron microscopy was used for the structural analysis of LyECs. Changes in LyEC phenotypes in livers of mice with I/R were determined by RNA-seq analysis. Results Through scRNA-seq analysis, we have identified IL7 as an exclusive marker for liver LyECs, with no overlap with other liver cell types. Based on IL7 expression in liver LyECs, we have established an LyEC isolation method and observed distinct cell surface structures of LyECs with fenestrae and cellular pores (ranging from 100 to 400 nm in diameter). Furthermore, we identified LyEC genes that undergo alterations during I/R liver injuries. Conclusions This study not only identified IL7 as an exclusively expressed gene in liver LyECs, but also enhanced our understanding of LyEC structures and demonstrated transcriptomic changes in injured livers. Impact and implications Understanding the lymphatic system in the liver is challenging because of the absence of specific markers for liver LyEC. This study has identified IL7 as a reliable marker for LyECs, enabling the development of an effective method for their isolation, elucidating their unique cell surface structure, and identifying LyEC genes that undergo changes during liver damage. The development of IL7 antibodies for detecting it in human liver specimens will further advance our understanding of the liver lymphatic system in the future.
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Affiliation(s)
- Yilin Yang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Tingting Su
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
- Department of Gastroenterology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Sanchuan Lai
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
- Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Pengpeng Zhang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
- The Transplantation Center of the Third Xiangya Hospital, Central South University, Changsha, China
| | - Rolando Garcia-Milian
- Bioinformatics Support Hub, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Morven Graham
- Center for Cellular and Molecular Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Xinran Liu
- Center for Cellular and Molecular Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Matthew J. McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Teruo Utsumi
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Joao Pereira
- Department of Immunobiology and Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
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8
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Park C, Hwang IY, Yan SLS, Vimonpatranon S, Wei D, Van Ryk D, Girard A, Cicala C, Arthos J, Kehrl JH. Murine alveolar macrophages rapidly accumulate intranasally administered SARS-CoV-2 Spike protein leading to neutrophil recruitment and damage. eLife 2024; 12:RP86764. [PMID: 38507462 PMCID: PMC10954308 DOI: 10.7554/elife.86764] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024] Open
Abstract
The trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike protein in vivo and its impact on immune cells remains incompletely elucidated. In this study, we inoculated mice intranasally, intravenously, and subcutaneously with fluorescently labeled recombinant SARS-CoV-2 Spike protein. Using flow cytometry and imaging techniques, we analyzed its localization, immune cell tropism, and acute functional impact. Intranasal administration led to rapid lung alveolar macrophage uptake, pulmonary vascular leakage, and neutrophil recruitment and damage. When injected near the inguinal lymph node medullary, but not subcapsular macrophages, captured the protein, while scrotal injection recruited and fragmented neutrophils. Widespread endothelial and liver Kupffer cell uptake followed intravenous administration. Human peripheral blood cells B cells, neutrophils, monocytes, and myeloid dendritic cells all efficiently bound Spike protein. Exposure to the Spike protein enhanced neutrophil NETosis and augmented human macrophage TNF-α (tumor necrosis factor-α) and IL-6 production. Human and murine immune cells employed C-type lectin receptors and Siglecs to help capture the Spike protein. This study highlights the potential toxicity of the SARS-CoV-2 Spike protein for mammalian cells and illustrates the central role for alveolar macrophage in pathogenic protein uptake.
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Affiliation(s)
- Chung Park
- B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUnited States
| | - Il-Young Hwang
- B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUnited States
| | - Serena Li-Sue Yan
- B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUnited States
| | - Sinmanus Vimonpatranon
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesBethesdaUnited States
- Department of Retrovirology, Armed Forces Research Institute of Medical Sciences – United States ComponentBangkokThailand
| | - Danlan Wei
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Don Van Ryk
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Alexandre Girard
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - Claudia Cicala
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - James Arthos
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious DiseasesBethesdaUnited States
| | - John H Kehrl
- B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUnited States
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9
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Szafranska K, Sørensen KK, Lalor PF, McCourt P. Sinusoidal cells and liver immunology. SINUSOIDAL CELLS IN LIVER DISEASES 2024:53-75. [DOI: 10.1016/b978-0-323-95262-0.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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10
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Park C, Hwang IY, Yan SLS, Vimonpatranon S, Wei D, Van Ryk D, Girard A, Cicala C, Arthos J, Kehrl JH. Murine Alveolar Macrophages Rapidly Accumulate Intranasally Administered SARS-CoV-2 Spike Protein leading to Neutrophil Recruitment and Damage. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.13.532446. [PMID: 37090605 PMCID: PMC10120727 DOI: 10.1101/2023.03.13.532446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
The trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike protein in vivo and its impact on immune cells remains incompletely elucidated. In this study we inoculated mice intranasally, intravenously, and subcutaneously with fluorescently labeled recombinant SARS-CoV-2 Spike protein. Using flow cytometry and imaging techniques we analyzed its localization, immune cell tropism, and acute functional impact. Intranasal administration led to rapid lung alveolar macrophage uptake, pulmonary vascular leakage, and neutrophil recruitment and damage. When injected near the inguinal lymph node medullary, but not subcapsular macrophages, captured the protein, while scrotal injection recruited and fragmented neutrophils. Wide-spread endothelial and liver Kupffer cell uptake followed intravenous administration. Human peripheral blood cells B cells, neutrophils, monocytes, and myeloid dendritic cells all efficiently bound Spike protein. Exposure to the Spike protein enhanced neutrophil NETosis and augmented human macrophage TNF-α and IL-6 production. Human and murine immune cells employed C-type lectin receptors and Siglecs to help capture the Spike protein. This study highlights the potential toxicity of the SARS-CoV-2 Spike protein for mammalian cells and illustrates the central role for alveolar macrophage in pathogenic protein uptake.
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Affiliation(s)
- Chung Park
- B-cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Il-Young Hwang
- B-cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Serena Li-Sue Yan
- B-cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
| | - Sinmanus Vimonpatranon
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
- Department of Retrovirology, Armed Forces Research Institute of Medical Sciences – United States Component, Bangkok, Thailand
| | - Danlan Wei
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Don Van Ryk
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Alexandre Girard
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - Claudia Cicala
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - James Arthos
- Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, United States of America
| | - John H. Kehrl
- B-cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
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11
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Kyrrestad I, Larsen AK, Sánchez Romano J, Simón-Santamaría J, Li R, Sørensen KK. Infection of liver sinusoidal endothelial cells with Muromegalovirus muridbeta1 involves binding to neuropilin-1 and is dynamin-dependent. Front Cell Infect Microbiol 2023; 13:1249894. [PMID: 38029264 PMCID: PMC10665495 DOI: 10.3389/fcimb.2023.1249894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSEC) are scavenger cells with a remarkably high capacity for clearance of several blood-borne macromolecules and nanoparticles, including some viruses. Endocytosis in LSEC is mainly via the clathrin-coated pit mediated route, which is dynamin-dependent. LSEC can also be a site of infection and latency of betaherpesvirus, but mode of virus entry into these cells has not yet been described. In this study we have investigated the role of dynamin in the early stage of muromegalovirus muridbeta1 (MuHV-1, murid betaherpesvirus 1, murine cytomegalovirus) infection in mouse LSECs. LSEC cultures were freshly prepared from C57Bl/6JRj mouse liver. We first examined dose- and time-dependent effects of two dynamin-inhibitors, dynasore and MitMAB, on cell viability, morphology, and endocytosis of model ligands via different LSEC scavenger receptors to establish a protocol for dynamin-inhibition studies in these primary cells. LSECs were challenged with MuHV-1 (MOI 0.2) ± dynamin inhibitors for 1h, then without inhibitors and virus for 11h, and nuclear expression of MuHV-1 immediate early antigen (IE1) measured by immune fluorescence. MuHV-1 efficiently infected LSECs in vitro. Infection was significantly and independently inhibited by dynasore and MitMAB, which block dynamin function via different mechanisms, suggesting that initial steps of MuHV-1 infection is dynamin-dependent in LSECs. Infection was also reduced in the presence of monensin which inhibits acidification of endosomes. Furthermore, competitive binding studies with a neuropilin-1 antibody blocked LSEC infection. This suggests that MuHV-1 infection in mouse LSECs involves virus binding to neuropilin-1 and occurs via endocytosis.
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Affiliation(s)
- Ingelin Kyrrestad
- Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway
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12
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Furini G, De Carli A, Fonnesu R, Spezia PG, Scebba F, Pistello M, Lai M, Lionetti V. Gene silencing of endothelial von Willebrand factor reduces the susceptibility of human endothelial cells to SARS-CoV-2 infection. FEBS J 2023; 290:4300-4315. [PMID: 37098810 DOI: 10.1111/febs.16808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 03/03/2023] [Accepted: 04/25/2023] [Indexed: 04/27/2023]
Abstract
Mechanisms underlying vascular endothelial susceptibility to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not fully understood. Emerging evidence indicates that patients lacking von Willebrand factor (vWF), an endothelial hallmark, are less severely affected by SARS-CoV-2 infection, yet the precise role of endothelial vWF in modulating coronavirus entry into endothelial cells is unknown. In the present study, we demonstrated that effective gene silencing by short interfering RNA (siRNA) for vWF expression in resting human umbilical vein endothelial cells (HUVECs) significantly reduced by 56% the cellular levels of SARS-CoV-2 genomic RNA. Similar reduction in intracellular SARS-CoV-2 genomic RNA levels was observed in non-activated HUVECs treated with siRNA targeting angiotensin-converting enzyme 2 (ACE2), the cellular gateway to coronavirus. By integrating quantitative information from real-time PCR and high-resolution confocal imaging, we demonstrated that ACE2 gene expression and its plasma membrane localization in HUVECs were both markedly reduced after treatment with siRNA anti-vWF or anti-ACE2. Conversely, siRNA anti-ACE2 did not reduce endothelial vWF gene expression and protein levels. Finally, SARS-CoV-2 infection of viable HUVECs was enhanced by overexpression of vWF, which increased ACE2 levels. Of note, we found a similar increase in interferon-β mRNA levels following transfection with untargeted, anti-vWF or anti-ACE2 siRNA and pcDNA3.1-WT-VWF. We envision that siRNA targeting endothelial vWF will protect against productive endothelial infection by SARS-CoV-2 through downregulation of ACE2 expression and might serve as a novel tool to induce disease resistance by modulating the regulatory role of vWF on ACE2 expression.
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Affiliation(s)
- Giulia Furini
- Unit of Translational Critical Care Medicine, Laboratory of Basic and Applied Medical Sciences, Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
- UOSVD Anesthesia and Resuscitation, Fondazione Toscana "G. Monasterio", Pisa, Italy
| | - Alessandro De Carli
- Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, Retrovirus Center, University of Pisa, Italy
| | - Rossella Fonnesu
- Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, Retrovirus Center, University of Pisa, Italy
| | - Pietro Giorgio Spezia
- Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, Retrovirus Center, University of Pisa, Italy
| | - Francesca Scebba
- BioMedicine Laboratory, Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
| | - Mauro Pistello
- Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, Retrovirus Center, University of Pisa, Italy
- Virology Unit, Pisa University Hospital, Italy
| | - Michele Lai
- Virology Section, Department of Translational Research and New Technologies in Medicine and Surgery, Retrovirus Center, University of Pisa, Italy
- CISUP - Centre for Instrumentation Sharing - University of Pisa, Italy
| | - Vincenzo Lionetti
- Unit of Translational Critical Care Medicine, Laboratory of Basic and Applied Medical Sciences, Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
- UOSVD Anesthesia and Resuscitation, Fondazione Toscana "G. Monasterio", Pisa, Italy
- BioMedicine Laboratory, Interdisciplinary Research Center "Health Science", Scuola Superiore Sant'Anna, Pisa, Italy
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13
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Alboni S, Secco V, Papotti B, Vilella A, Adorni MP, Zimetti F, Schaeffer L, Tascedda F, Zoli M, Leblanc P, Villa E. Hydroxypropyl-β-Cyclodextrin Depletes Membrane Cholesterol and Inhibits SARS-CoV-2 Entry into HEK293T-ACE hi Cells. Pathogens 2023; 12:pathogens12050647. [PMID: 37242317 DOI: 10.3390/pathogens12050647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/23/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Vaccination has drastically decreased mortality due to coronavirus disease 19 (COVID-19), but not the rate of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Alternative strategies such as inhibition of virus entry by interference with angiotensin-I-converting enzyme 2 (ACE2) receptors could be warranted. Cyclodextrins (CDs) are cyclic oligosaccharides that are able to deplete cholesterol from membrane lipid rafts, causing ACE2 receptors to relocate to areas devoid of lipid rafts. To explore the possibility of reducing SARS-CoV-2 entry, we tested hydroxypropyl-β-cyclodextrin (HPβCD) in a HEK293T-ACE2hi cell line stably overexpressing human ACE2 and Spike-pseudotyped SARS-CoV-2 lentiviral particles. We showed that HPβCD is not toxic to the cells at concentrations up to 5 mM, and that this concentration had no significant effect on cell cycle parameters in any experimental condition tested. Exposure of HEK293T-ACEhi cells to concentrations of HPβCD starting from 2.5 mM to 10 mM showed a concentration-dependent reduction of approximately 50% of the membrane cholesterol content. In addition, incubation of HEK293T-ACEhi cells with HIV-S-CoV-2 pseudotyped particles in the presence of increasing concentrations of HPβCD (from 0.1 to 10 mM) displayed a concentration-dependent effect on SARS-CoV-2 entry efficiency. Significant effects were detected at concentrations at least one order of magnitude lower than the lowest concentration showing toxic effects. These data indicate that HPβCD is a candidate for use as a SARS-CoV-2 prophylactic agent.
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Affiliation(s)
- Silvia Alboni
- Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
- Centre for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Valentina Secco
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Bianca Papotti
- Department of Food and Drug, University of Parma, 43124 Parma, Italy
| | - Antonietta Vilella
- Centre for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41121 Modena, Italy
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Maria Pia Adorni
- Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
| | - Francesca Zimetti
- Department of Food and Drug, University of Parma, 43124 Parma, Italy
| | - Laurent Schaeffer
- Institut NeuroMyoGène INMG-PGNM Pathophysiologie & Génétique du Neurone et du Muscle, UMR5261, Inserm U1315, 69008 Lyon, France
| | - Fabio Tascedda
- Department of Life Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
- Centre for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41121 Modena, Italy
- Consorzio Interuniversitario Biotecnologie (CIB), 34148 Trieste, Italy
| | - Michele Zoli
- Centre for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, 41121 Modena, Italy
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41121 Modena, Italy
| | - Pascal Leblanc
- Institut NeuroMyoGène INMG-PGNM Pathophysiologie & Génétique du Neurone et du Muscle, UMR5261, Inserm U1315, 69008 Lyon, France
| | - Erica Villa
- CHIMOMO Department, University of Modena and Reggio Emilia, and Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy
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14
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Porkolab V, Lepšík M, Ordanini S, St John A, Le Roy A, Thépaut M, Paci E, Ebel C, Bernardi A, Fieschi F. Powerful Avidity with a Limited Valency for Virus-Attachment Blockers on DC-SIGN: Combining Chelation and Statistical Rebinding with Structural Plasticity of the Receptor. ACS CENTRAL SCIENCE 2023; 9:709-718. [PMID: 37122470 PMCID: PMC10141607 DOI: 10.1021/acscentsci.2c01136] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Indexed: 05/03/2023]
Abstract
The C-type lectin receptor DC-SIGN has been highlighted as the coreceptor for the spike protein of the SARS-CoV-2 virus. A multivalent glycomimetic ligand, Polyman26, has been found to inhibit DC-SIGN-dependent trans-infection of SARS-CoV-2. The molecular details underlying avidity generation in such systems remain poorly characterized. In an effort to dissect the contribution of the known multivalent effects - chelation, clustering, and statistical rebinding - we studied a series of dendrimer constructs related to Polyman26 with a rod core rationally designed to engage simultaneously two binding sites of the tetrameric DC-SIGN. Binding properties of these compounds have been studied with a range of biophysical techniques, including recently developed surface plasmon resonance oriented-surface methodology. Using molecular modeling we addressed, for the first time, the impact of the carbohydrate recognition domains' flexibility of the DC-SIGN tetramer on the compounds' avidity. We were able to gain deeper insight into the role of different binding modes, which in combination produce a construct with a nanomolar affinity despite a limited valency. This multifaceted experimental-theoretical approach provides detailed understanding of multivalent ligand/multimeric protein interactions which can lead to future predictions. This work opens the way to the development of new virus attachment blockers adapted to different C-type lectin receptors of viruses.
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Affiliation(s)
- Vanessa Porkolab
- Univ.
Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France
| | - Martin Lepšík
- Univ.
Grenoble Alpes, CNRS, CERMAV, 38000 Grenoble, France
- Institute
of Organic Chemistry and Biochemistry, Czech
Academy of Sciences, Flemingovo nam. 2, Prague 6, 166 10, Czechia
| | - Stefania Ordanini
- Universita’
degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133, Milano, Italy
| | - Alexander St John
- Astbury
Centre & School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Aline Le Roy
- Univ.
Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France
| | - Michel Thépaut
- Univ.
Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France
| | - Emanuele Paci
- Department
of Physics and Astronomy “Augusto Righi”, University of Bologna, Via Zamboni, 33, 40126, Bologna, Italy
| | - Christine Ebel
- Univ.
Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France
| | - Anna Bernardi
- Universita’
degli Studi di Milano, Dipartimento di Chimica, via Golgi 19, 20133, Milano, Italy
| | - Franck Fieschi
- Univ.
Grenoble Alpes, CNRS, CEA, Institut de Biologie Structurale, 38000 Grenoble, France
- Institut
Universitaire de France (IUF), 1 rue Descartes, 75231 Paris, France
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15
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Xu SW, Ilyas I, Weng JP. Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies. Acta Pharmacol Sin 2023; 44:695-709. [PMID: 36253560 PMCID: PMC9574180 DOI: 10.1038/s41401-022-00998-0] [Citation(s) in RCA: 183] [Impact Index Per Article: 91.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 09/11/2022] [Indexed: 12/15/2022]
Abstract
The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.
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Affiliation(s)
- Suo-Wen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China.
| | - Iqra Ilyas
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China
| | - Jian-Ping Weng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China.
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16
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Matsumoto C, Shibata S, Kishi T, Morimoto S, Mogi M, Yamamoto K, Kobayashi K, Tanaka M, Asayama K, Yamamoto E, Nakagami H, Hoshide S, Mukoyama M, Kario K, Node K, Rakugi H. Long COVID and hypertension-related disorders: a report from the Japanese Society of Hypertension Project Team on COVID-19. Hypertens Res 2023; 46:601-619. [PMID: 36575228 PMCID: PMC9793823 DOI: 10.1038/s41440-022-01145-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/28/2022]
Abstract
The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.
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Affiliation(s)
- Chisa Matsumoto
- Department of Cardiology, Preventive medicine, Tokyo Medical University, Tokyo, Japan.
| | - Shigeru Shibata
- Division of Nephrology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.
| | - Takuya Kishi
- Department of Graduate School of Medicine (Cardiology), International University of Health and Welfare, Okawa, Japan
| | - Satoshi Morimoto
- Department of Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo, Japan
| | - Masaki Mogi
- Department of Pharmacology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Koichi Yamamoto
- Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazuo Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Kobayashi Internal Medicine Clinic, Sagamihara, Japan
| | - Masami Tanaka
- Department of Internal Medicine, Adachi Medical Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Kei Asayama
- Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan
| | - Eiichiro Yamamoto
- Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Hironori Nakagami
- Department of Health Development and Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan
| | - Satoshi Hoshide
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Masashi Mukoyama
- Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
| | - Kazuomi Kario
- Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, Saga, Japan
| | - Hiromi Rakugi
- Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
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17
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Avdonin PP, Rybakova EY, Trufanov SK, Avdonin PV. SARS-CoV-2 Receptors and Their Involvement in Cell Infection. BIOCHEMISTRY (MOSCOW), SUPPLEMENT SERIES A: MEMBRANE AND CELL BIOLOGY 2023; 17:1-11. [PMID: 37008884 PMCID: PMC10050803 DOI: 10.1134/s1990747822060034] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 07/30/2022] [Accepted: 08/01/2022] [Indexed: 03/30/2023]
Abstract
The new coronavirus infection (COVID-19) pandemic caused by SARS-CoV-2 has many times surpassed the epidemics caused by SARS-CoV and MERS-CoV. The reason for this was the presence of sites in the protein sequence of SARS-CoV-2 that provide interaction with a broader range of receptor proteins on the host cell surface. In this review, we consider both already known receptors common to SARS-CoV and SARS-CoV-2 and new receptors specific to SARS-CoV-2.
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Affiliation(s)
- P. P. Avdonin
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - E. Yu. Rybakova
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - S. K. Trufanov
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - P. V. Avdonin
- N.K. Koltsov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
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18
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Shilts J, Crozier TWM, Teixeira-Silva A, Gabaev I, Gerber PP, Greenwood EJD, Watson SJ, Ortmann BM, Gawden-Bone CM, Pauzaite T, Hoffmann M, Nathan JA, Pöhlmann S, Matheson NJ, Lehner PJ, Wright GJ. LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein. PLoS Biol 2023; 21:e3001959. [PMID: 36735681 PMCID: PMC9897555 DOI: 10.1371/journal.pbio.3001959] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/14/2022] [Indexed: 02/04/2023] Open
Abstract
The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.
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Affiliation(s)
- Jarrod Shilts
- Cell Surface Signalling Laboratory, Wellcome Sanger Institute, Cambridge, United Kingdom
- Department of Biology, Hull York Medical School, York Biomedical Research Institute, University of York, York, United Kingdom
| | - Thomas W. M. Crozier
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Ana Teixeira-Silva
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Ildar Gabaev
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Pehuén Pereyra Gerber
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Edward J. D. Greenwood
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Samuel James Watson
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Brian M. Ortmann
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Christian M. Gawden-Bone
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Tekle Pauzaite
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Markus Hoffmann
- Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, Göttingen, Germany
- Faculty of Biology and Psychology, Georg-August University Göttingen, Göttingen, Germany
| | - James A. Nathan
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, Göttingen, Germany
- Faculty of Biology and Psychology, Georg-August University Göttingen, Göttingen, Germany
| | - Nicholas J. Matheson
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
- NHS Blood and Transplant, Cambridge, United Kingdom
| | - Paul J. Lehner
- Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom
| | - Gavin J. Wright
- Cell Surface Signalling Laboratory, Wellcome Sanger Institute, Cambridge, United Kingdom
- Department of Biology, Hull York Medical School, York Biomedical Research Institute, University of York, York, United Kingdom
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19
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Bräutigam K, Reinhard S, Wartenberg M, Forster S, Greif K, Granai M, Bösmüller H, Klingel K, Schürch CM. Comprehensive analysis of SARS-CoV-2 receptor proteins in human respiratory tissues identifies alveolar macrophages as potential virus entry site. Histopathology 2023; 82:846-859. [PMID: 36700825 DOI: 10.1111/his.14871] [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: 09/12/2022] [Revised: 01/15/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023]
Abstract
AIMS COVID-19 has had enormous consequences on global health-care and has resulted in millions of fatalities. The exact mechanism and site of SARS-CoV-2 entry into the body remains insufficiently understood. Recently, novel virus receptors were identified, and alveolar macrophages were suggested as a potential viral entry cell type and vector for intra-alveolar virus transmission. Here, we investigated the protein expression of 10 well-known and novel virus entry molecules along potential entry sites in humans using immunohistochemistry. METHODS AND RESULTS Samples of different anatomical sites from up to 93 patients were incorporated into tissue microarrays. Protein expression of ACE2, TMPRSS2, furin, CD147, C-type lectin receptors (CD169, CD209, CD299), neuropilin-1, ASGR1 and KREMEN1 were analysed. In lung tissues, at least one of the three receptors ACE2, ASGR1 or KREMEN1 was expressed in the majority of cases. Moreover, all the investigated molecules were found to be expressed in alveolar macrophages, and co-localisation with SARS-CoV-2 N-protein was demonstrated using dual immunohistochemistry in lung tissue from a COVID-19 autopsy. While CD169 and CD209 showed consistent protein expression in sinonasal, conjunctival and bronchiolar tissues, neuropilin-1 and ASGR1 were mostly absent, suggesting a minor relevance of these two molecules at these specific sites. CONCLUSION Our results extend recent discoveries indicating a role for these molecules in virus entry at different anatomical sites. Moreover, they support the notion of alveolar macrophages being a potential entry cell for SARS-CoV-2.
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Affiliation(s)
| | - Stefan Reinhard
- Institute of Pathology, University of Bern, Bern, Switzerland
| | | | - Stefan Forster
- Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Karen Greif
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Massimo Granai
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Hans Bösmüller
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Karin Klingel
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Christian M Schürch
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
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20
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Hu WS, Jiang FY, Shu W, Zhao R, Cao JM, Wang DP. Liver injury in COVID-19: A minireview. World J Gastroenterol 2022; 28:6716-6731. [PMID: 36620342 PMCID: PMC9813934 DOI: 10.3748/wjg.v28.i47.6716] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/02/2022] [Accepted: 11/23/2022] [Indexed: 12/19/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has escalated into a global tragedy afflicting human health, life, and social governance. Through the increasing depth of research and a better understanding of this disease, it has been ascertained that, in addition to the lungs, SARS-CoV-2 can also induce injuries to other organs including the liver. Liver injury is a common clinical manifestation of COVID-19, particularly in severe cases, and is often associated with a poorer prognosis and higher severity of COVID-19. This review focuses on the general existing information on liver injury caused by COVID-19, including risk factors and subpopulations of liver injury in COVID-19, the association between preexisting liver diseases and the severity of COVID-19, and the potential mechanisms by which SARS-CoV-2 affects the liver. This review may provide some useful information for the development of therapeutic and preventive strategies for COVID-19-associated liver injury.
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Affiliation(s)
- Wen-Shu Hu
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Fang-Ying Jiang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Wen Shu
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Rong Zhao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Ji-Min Cao
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - De-Ping Wang
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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21
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Genetic variants determine intrafamilial variability of SARS-CoV-2 clinical outcomes in 19 Italian families. PLoS One 2022; 17:e0275988. [PMID: 36228008 PMCID: PMC9560599 DOI: 10.1371/journal.pone.0275988] [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: 03/09/2022] [Accepted: 09/27/2022] [Indexed: 11/07/2022] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in a wide range of outcomes characterized by a high heterogeneity in both symptomatology and susceptibility to the disease. In such a perspective, COVID-19 may be considered as a multifactorial disease featured by the interaction between the environment, which is the virus itself, and the genetic profile of the host. Our analysis aimed at investigating the transmission dynamics of SARS-CoV-2 within families whose members responded in different ways to the infection, although the exposure was common to the entire group and occurred before the availability of any vaccine. The goal was to understand how the genetic background of each subject can influence the viral infection outcome and hence the above-mentioned clinical variability. We performed a segregation analysis in 19 Italian families with a designed custom panel of 42 genes involved in immunity and virus entry and which have also been shown to be related to SARS-CoV-2 host response. We carried out both a familial segregation analysis and a global statistical analysis. In the former we identified eighteen risk variants co-segregating with a COVID-positive status and six variants with a possible protective effect. In addition, sixteen variants showed a trend of association to a severe phenotype. Together with common SNPs, we detected private rare variants that may also provide insight into the observed clinical COVID-19 heterogeneity. The global statistical analysis confirmed statistically significant positive associations between SARS-CoV-2 individual response and some specific gene variants identified in familial analysis. In conclusion our data confirm that the clinical expression of COVID-19 is markedly influenced by the host genetic profile both with a mendelian transmission pattern and a polygenic architecture.
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22
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Li P, Liu Y, Cheng Z, Yu X, Li Y. COVID-19-associated liver injury: Clinical characteristics, pathophysiological mechanisms and treatment management. Biomed Pharmacother 2022; 154:113568. [PMID: 36029543 PMCID: PMC9381432 DOI: 10.1016/j.biopha.2022.113568] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/14/2022] [Accepted: 08/15/2022] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global epidemic and poses a major threat to public health. In addition to COVID-19 manifesting as a respiratory disease, patients with severe disease also have complications in extrapulmonary organs, including liver damage. Abnormal liver function is relatively common in COVID-19 patients; its clinical manifestations can range from an asymptomatic elevation of liver enzymes to decompensated hepatic function, and liver injury is more prevalent in severe and critical patients. Liver injury in COVID-19 patients is a comprehensive effect mediated by multiple factors, including liver damage directly caused by SARS-CoV-2, drug-induced liver damage, hypoxia reperfusion dysfunction, immune stress and inflammatory factor storms. Patients with chronic liver disease (especially alcohol-related liver disease, nonalcoholic fatty liver disease, cirrhosis and hepatocellular carcinoma) are at increased risk of severe disease and death after infection with SARS-CoV-2, and COVID-19 aggravates liver damage in patients with chronic liver disease. This article reviews the latest SARS-CoV-2 reports, focusing on the liver damage caused by COVID-19 and the underlying mechanism, and expounds on the risk, treatment and vaccine safety of SARS-CoV-2 in patients with chronic liver disease and liver transplantation.
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Affiliation(s)
- Penghui Li
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Ying Liu
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Ziqi Cheng
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xiaorui Yu
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yinxiong Li
- Center for Health Research, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Key Laboratory of Stem Cell and Regenerative Medicine, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; State Key Laboratory of Respiratory Disease, Guangzhou, China; China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, China.
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23
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Farhangnia P, Dehrouyeh S, Safdarian AR, Farahani SV, Gorgani M, Rezaei N, Akbarpour M, Delbandi AA. Recent advances in passive immunotherapies for COVID-19: The Evidence-Based approaches and clinical trials. Int Immunopharmacol 2022; 109:108786. [PMID: 35483235 PMCID: PMC9021130 DOI: 10.1016/j.intimp.2022.108786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 04/14/2022] [Accepted: 04/16/2022] [Indexed: 12/15/2022]
Abstract
In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, causing a global pandemic called COVID-19. Currently, there is no definitive treatment for this emerging disease. Global efforts resulted in developing multiple platforms of COVID-19 vaccines, but their efficacy in humans should be wholly investigated in the long-term clinical and epidemiological follow-ups. Despite the international efforts, COVID-19 vaccination accompanies challenges, including financial and political obstacles, serious adverse effects (AEs), the impossibility of using vaccines in certain groups of people in the community, and viral evasion due to emerging novel variants of SARS-CoV-2 in many countries. For these reasons, passive immunotherapy has been considered a complementary remedy and a promising way to manage COVID-19. These approaches arebased on reduced inflammation due to inhibiting cytokine storm phenomena, immunomodulation,preventing acute respiratory distress syndrome (ARDS), viral neutralization, anddecreased viral load. This article highlights passive immunotherapy and immunomodulation approaches in managing and treating COVID-19 patients and discusses relevant clinical trials (CTs).
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Affiliation(s)
- Pooya Farhangnia
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Chicago, United States
| | - Shiva Dehrouyeh
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Chicago, United States
| | - Amir Reza Safdarian
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Chicago, United States; Department of Pathology, School of Medicine, Alborz University of Medical Sciences, Alborz, Iran
| | - Soheila Vasheghani Farahani
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Chicago, United States; Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Melika Gorgani
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Chicago, United States
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahzad Akbarpour
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Chicago, United States; Advanced Cellular Therapeutics Facility (ACTF), Hematopoietic Cellular Therapy Program, Section of Hematology & Oncology, Department of Medicine, University of Chicago Medical Center, Chicago, United States.
| | - Ali-Akbar Delbandi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Immunology Research Center, Institute of Immunology and Infectious Disease, Iran University of Medical Sciences, Tehran, Iran.
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24
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Tokarczyk U, Kaliszewski K, Kopszak A, Nowak Ł, Sutkowska-Stępień K, Sroczyński M, Sępek M, Dudek A, Diakowska D, Trocha M, Gajecki D, Gawryś J, Matys T, Maciejiczek J, Kozub V, Szalast R, Madziarski M, Zubkiewicz-Zarębska A, Letachowicz K, Kiliś-Pstrusińska K, Matera-Witkiewicz A, Pomorski M, Protasiewicz M, Sokołowski J, Adamik B, Kujawa K, Doroszko A, Madziarska K, Jankowska EA. Liver Function Tests in COVID-19: Assessment of the Actual Prognostic Value. J Clin Med 2022; 11:jcm11154490. [PMID: 35956107 PMCID: PMC9369475 DOI: 10.3390/jcm11154490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 01/08/2023] Open
Abstract
Deviations in laboratory tests assessing liver function in patients with COVID-19 are frequently observed. Their importance and pathogenesis are still debated. In our retrospective study, we analyzed liver-related parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), albumin, comorbidities and other selected potential risk factors in patients admitted with SARS-CoV-2 infection to assess their prognostic value for intensive care unit admission, mechanical ventilation necessity and mortality. We compared the prognostic effectiveness of these parameters separately and in pairs to the neutrophil-to-lymphocyte ratio (NLR) as an independent risk factor of in-hospital mortality, using the Akaike Information Criterion (AIC). Data were collected from 2109 included patients. We created models using a sample with complete laboratory tests n = 401 and then applied them to the whole studied group excluding patients with missing singular variables. We estimated that albumin may be a better predictor of the COVID-19-severity course compared to NLR, irrespective of comorbidities (p < 0.001). Additionally, we determined that hypoalbuminemia in combination with AST (OR 1.003, p = 0.008) or TBIL (OR 1.657, p = 0.001) creates excellent prediction models for in-hospital mortality. In conclusion, the early evaluation of albumin levels and liver-related parameters may be indispensable tools for the early assessment of the clinical course of patients with COVID-19.
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Affiliation(s)
- Urszula Tokarczyk
- Clinical Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.S.-S.); (M.S.); (M.S.); (A.D.)
- Correspondence: (U.T.); (K.K.); Tel.: +48-723-781-491 (U.T.); +48-71-734-30-00 (K.K.); Fax: +48-71-734-30-00 (K.K.)
| | - Krzysztof Kaliszewski
- Clinical Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.S.-S.); (M.S.); (M.S.); (A.D.)
- Correspondence: (U.T.); (K.K.); Tel.: +48-723-781-491 (U.T.); +48-71-734-30-00 (K.K.); Fax: +48-71-734-30-00 (K.K.)
| | - Anna Kopszak
- Statistical Analysis Center, Wroclaw Medical University, Marcinkowski Street 2-6, 50-368 Wroclaw, Poland; (A.K.); (K.K.)
| | - Łukasz Nowak
- Clinical Department of Urology and Urological Oncology, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Karolina Sutkowska-Stępień
- Clinical Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.S.-S.); (M.S.); (M.S.); (A.D.)
| | - Maciej Sroczyński
- Clinical Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.S.-S.); (M.S.); (M.S.); (A.D.)
| | - Monika Sępek
- Clinical Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.S.-S.); (M.S.); (M.S.); (A.D.)
| | - Agata Dudek
- Clinical Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.S.-S.); (M.S.); (M.S.); (A.D.)
| | - Dorota Diakowska
- Department of Basic Science, Faculty of Health Science, Wroclaw Medical University, Bartel Street 5, 51-618 Wroclaw, Poland;
| | - Małgorzata Trocha
- Department of Pharmacology, Wroclaw Medical University, Mikulicz-Radecki Street 2, 50-345 Wroclaw, Poland;
| | - Damian Gajecki
- Clinical Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (D.G.); (J.G.); (T.M.); (A.D.)
| | - Jakub Gawryś
- Clinical Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (D.G.); (J.G.); (T.M.); (A.D.)
| | - Tomasz Matys
- Clinical Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (D.G.); (J.G.); (T.M.); (A.D.)
| | - Justyna Maciejiczek
- Clinical Department of Internal Medicine, Pneumology and Allergology, Wroclaw Medical University, M. Skłodowskiej-Curie Street 66, 50-369 Wroclaw, Poland; (J.M.); (V.K.); (R.S.)
| | - Valeriia Kozub
- Clinical Department of Internal Medicine, Pneumology and Allergology, Wroclaw Medical University, M. Skłodowskiej-Curie Street 66, 50-369 Wroclaw, Poland; (J.M.); (V.K.); (R.S.)
| | - Roman Szalast
- Clinical Department of Internal Medicine, Pneumology and Allergology, Wroclaw Medical University, M. Skłodowskiej-Curie Street 66, 50-369 Wroclaw, Poland; (J.M.); (V.K.); (R.S.)
| | - Marcin Madziarski
- Clinical Department of Rheumatology and Internal Medicine, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Anna Zubkiewicz-Zarębska
- Clinical Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Krzysztof Letachowicz
- Clinical Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.L.); (K.M.)
| | - Katarzyna Kiliś-Pstrusińska
- Clinical Department of Pediatric Nephrology, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Agnieszka Matera-Witkiewicz
- Screening Laboratory of Biological Activity Assays and Collection of Biological Material, Faculty of Pharmacy, Wroclaw Medical University, Borowska Street 211A, 50-556 Wroclaw, Poland;
| | - Michał Pomorski
- Clinical Department of Gynecology and Obstetrics, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Marcin Protasiewicz
- Clinical Department and Clinic of Cardiology, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Janusz Sokołowski
- Department of Emergency Medicine, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Barbara Adamik
- Clinical Department of Anaesthesiology and Intensive Therapy, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
| | - Krzysztof Kujawa
- Statistical Analysis Center, Wroclaw Medical University, Marcinkowski Street 2-6, 50-368 Wroclaw, Poland; (A.K.); (K.K.)
| | - Adrian Doroszko
- Clinical Department of Internal and Occupational Diseases, Hypertension and Clinical Oncology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland; (D.G.); (J.G.); (T.M.); (A.D.)
| | - Katarzyna Madziarska
- Clinical Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (K.L.); (K.M.)
| | - Ewa Anita Jankowska
- University Hospital in Wroclaw, Institute of Heart Diseases, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland;
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25
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Roelle SM, Shukla N, Pham AT, Bruchez AM, Matreyek KA. Expanded ACE2 dependencies of diverse SARS-like coronavirus receptor binding domains. PLoS Biol 2022; 20:e3001738. [PMID: 35895696 PMCID: PMC9359572 DOI: 10.1371/journal.pbio.3001738] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 08/08/2022] [Accepted: 07/01/2022] [Indexed: 11/18/2022] Open
Abstract
Viral spillover from animal reservoirs can trigger public health crises and cripple the world economy. Knowing which viruses are primed for zoonotic transmission can focus surveillance efforts and mitigation strategies for future pandemics. Successful engagement of receptor protein orthologs is necessary during cross-species transmission. The clade 1 sarbecoviruses including Severe Acute Respiratory Syndrome-related Coronavirus (SARS-CoV) and SARS-CoV-2 enter cells via engagement of angiotensin converting enzyme-2 (ACE2), while the receptor for clade 2 and clade 3 remains largely uncharacterized. We developed a mixed cell pseudotyped virus infection assay to determine whether various clades 2 and 3 sarbecovirus spike proteins can enter HEK 293T cells expressing human or Rhinolophus horseshoe bat ACE2 proteins. The receptor binding domains from BtKY72 and Khosta-2 used human ACE2 for entry, while BtKY72 and Khosta-1 exhibited widespread use of diverse rhinolophid ACE2s. A lysine at ACE2 position 31 appeared to be a major determinant of the inability of these RBDs to use a certain ACE2 sequence. The ACE2 protein from Rhinolophus alcyone engaged all known clade 3 and clade 1 receptor binding domains. We observed little use of Rhinolophus ACE2 orthologs by the clade 2 viruses, supporting the likely use of a separate, unknown receptor. Our results suggest that clade 3 sarbecoviruses from Africa and Europe use Rhinolophus ACE2 for entry, and their spike proteins appear primed to contribute to zoonosis under the right conditions. Knowing which viruses are primed for zoonotic transmission can focus surveillance efforts and mitigation strategies for future pandemics. This study shows that SARS-like coronaviruses identified in bats from Europe and Africa can use a range of horseshoe bat ACE2s for entry. In addition, viruses found in Russia and Kenya also have the ability to at least weakly use human ACE2.
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Affiliation(s)
- Sarah M. Roelle
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Nidhi Shukla
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Anh T. Pham
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Anna M. Bruchez
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Kenneth A. Matreyek
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- * E-mail:
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26
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Farooq M, Khan AW, Ahmad B, Kim MS, Choi S. Therapeutic Targeting of Innate Immune Receptors Against SARS-CoV-2 Infection. Front Pharmacol 2022; 13:915565. [PMID: 35847031 PMCID: PMC9280161 DOI: 10.3389/fphar.2022.915565] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
The innate immune system is the first line of host's defense against invading pathogens. Multiple cellular sensors that detect viral components can induce innate antiviral immune responses. As a result, interferons and pro-inflammatory cytokines are produced which help in the elimination of invading viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to Coronaviridae family, and has a single-stranded, positive-sense RNA genome. It can infect multiple hosts; in humans, it is responsible for the novel coronavirus disease 2019 (COVID-19). Successful, timely, and appropriate detection of SARS-CoV-2 can be very important for the early generation of the immune response. Several drugs that target the innate immune receptors as well as other signaling molecules generated during the innate immune response are currently being investigated in clinical trials. In this review, we summarized the current knowledge of the mechanisms underlying host sensing and innate immune responses against SARS-CoV-2 infection, as well as the role of innate immune receptors in terms of their therapeutic potential against SARS-CoV-2. Moreover, we discussed the drugs undergoing clinical trials and the FDA approved drugs against SARS-CoV-2. This review will help in understanding the interactions between SARS-CoV-2 and innate immune receptors and thus will point towards new dimensions for the development of new therapeutics, which can be beneficial in the current pandemic.
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Affiliation(s)
- Mariya Farooq
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Ajou University, Suwon, South Korea
| | - Abdul Waheed Khan
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Bilal Ahmad
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Ajou University, Suwon, South Korea
| | - Moon Suk Kim
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, South Korea
- S&K Therapeutics, Ajou University, Suwon, South Korea
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27
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Yang S, Tong Y, Chen L, Yu W. Human Identical Sequences, hyaluronan, and hymecromone ─ the new mechanism and management of COVID-19. MOLECULAR BIOMEDICINE 2022; 3:15. [PMID: 35593963 PMCID: PMC9120813 DOI: 10.1186/s43556-022-00077-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/04/2022] [Indexed: 02/08/2023] Open
Abstract
COVID-19 caused by SARS-CoV-2 has created formidable damage to public health and market economy. Currently, SARS-CoV-2 variants has exacerbated the transmission from person-to-person. Even after a great deal of investigation on COVID-19, SARS-CoV-2 is still rampaging globally, emphasizing the urgent need to reformulate effective prevention and treatment strategies. Here, we review the latest research progress of COVID-19 and provide distinct perspectives on the mechanism and management of COVID-19. Specially, we highlight the significance of Human Identical Sequences (HIS), hyaluronan, and hymecromone ("Three-H") for the understanding and intervention of COVID-19. Firstly, HIS activate inflammation-related genes to influence COVID-19 progress through NamiRNA-Enhancer network. Accumulation of hyaluronan induced by HIS-mediated HAS2 upregulation is a substantial basis for clinical manifestations of COVID-19, especially in lymphocytopenia and pulmonary ground-glass opacity. Secondly, detection of plasma hyaluronan can be effective for evaluating the progression and severity of COVID-19. Thirdly, spike glycoprotein of SARS-CoV-2 may bind to hyaluronan and further serve as an allergen to stimulate allergic reaction, causing sudden adverse effects after vaccination or the aggravation of COVID-19. Finally, antisense oligonucleotides of HIS or inhibitors of hyaluronan synthesis (hymecromone) or antiallergic agents could be promising therapeutic agents for COVID-19. Collectively, Three-H could hold the key to understand the pathogenic mechanism and create effective therapeutic strategies for COVID-19.
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Affiliation(s)
- Shuai Yang
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China
| | - Ying Tong
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China
| | - Lu Chen
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China
| | - Wenqiang Yu
- Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences & Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.
- Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, People's Republic of China.
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28
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Eslami N, Aghbash PS, Shamekh A, Entezari-Maleki T, Nahand JS, Sales AJ, Baghi HB. SARS-CoV-2: Receptor and Co-receptor Tropism Probability. Curr Microbiol 2022; 79:133. [PMID: 35292865 PMCID: PMC8923825 DOI: 10.1007/s00284-022-02807-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
Abstract
The recent pandemic which arose from China, is caused by a pathogenic virus named "severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2)". Its rapid global expansion has inflicted an extreme public health concern. The attachment of receptor-binding domains (RBD) of the spike proteins (S) to the host cell's membrane, with or without the help of other cellular components such as proteases and especially co-receptors, is required for the first stage of its pathogenesis. In addition to humans, angiotensin-converting enzyme 2 (ACE2) is found on a wide range of vertebrate host's cellular surface. SARS-CoV-2 has a broad spectrum of tropism; thus, it can infect a vast range of tissues, organs, and hosts; even though the surface amino acids of the spike protein conflict in the receptor-binding region. Due to the heterogeneous ACE2 distribution and the presence of different domains on the SARS-CoV-2 spike protein for binding, the virus entry into diverse host cell types may depend on the host cells' receptor presentation with or without co-receptors. This review investigates multiple current types of receptor and co-receptor tropisms, with other molecular factors alongside their respective mechanisms, which facilitate the binding and entry of SARS-CoV-2 into the cells, extending the severity of the coronavirus disease 2019 (COVID-19). Understanding the pathogenesis of COVID-19 from this perspective can effectively help prevent this disease and provide more potent treatment strategies, particularly in vulnerable people with various cellular-level susceptibilities.
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Affiliation(s)
- Narges Eslami
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, 5166/15731, Tabriz, Iran
| | - Parisa Shiri Aghbash
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Shamekh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Taher Entezari-Maleki
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Jafari Sales
- Department of Microbiology School of Basic Sciences, Islamic Azad University, Kazerun BranchKazerun, Iran
| | - Hossein Bannazadeh Baghi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, 5166/15731, Tabriz, Iran.
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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29
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Gonçalves Júnior J. COVID-19, liver dysfunction and pathophysiology: A conceptual discussion. World J Gastroenterol 2022; 28:683-688. [PMID: 35317425 PMCID: PMC8900549 DOI: 10.3748/wjg.v28.i6.683] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/21/2021] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
The intra and extracellular pathways of hepatic injury by coronavirus disease 2019 (COVID-19) are still being studied. Understanding them is important to treat this viral disease and other liver and biliary tract disorders. Thus, this paper aims to present three hypotheses about liver injury caused by COVID-19: (1) The interactions between severe acute respiratory syndrome coronavirus 2 spike protein and membrane receptors in the hepatocyte; (2) The dysbiosis and “gut-liver axis” disruption in patients with serious clinical presentations of COVID-19; and (3) The inflammatory response exacerbated through the production of interleukins such as interleukin-6. However, despite these new perspectives, the pathophysiological process of liver injury caused by COVID-19 is still complex and multifactorial. Thus, understanding all these variables is a challenge to science but also the key to propose individualized and effective patient therapies.
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Affiliation(s)
- Jucier Gonçalves Júnior
- Department of Internal Medicine, Division of Rheumatology, São Paulo University, São Paulo 01246-903, State, Brazil
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30
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Guo L, Liang Y, Li H, Zheng H, Yang Z, Chen Y, Zhao X, Li J, Li B, Shi H, Sun M, Liu L. Epigenetic glycosylation of SARS-CoV-2 impact viral infection through DC&L-SIGN receptors. iScience 2021; 24:103426. [PMID: 34786539 PMCID: PMC8582233 DOI: 10.1016/j.isci.2021.103426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 10/06/2021] [Accepted: 11/08/2021] [Indexed: 01/06/2023] Open
Abstract
Glycosylation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein mediates viral entry and immune escape. While glycan site is determined by viral genetic code, glycosylation is completely dependent on host cell post-translational modification. Here, by producing SARS-CoV-2 virions from various host cell lines, viruses of different origins with diverse spike protein glycan patterns were revealed. Binding affinities to C-type lectin receptors (CLRs) DC&L-SIGN differed in the different glycan pattern virions. Although none of the CLRs supported viral productive infection, viral trans&cis-infection mediated by the CLRs were substantially changed among the different virions. Specifically, trans&cis-infection of virions with a high-mannose structure (Man5GlcNAc2) at the N1098 glycan site of the spike postfusion trimer were markedly enhanced. Considering L-SIGN co-expression with ACE2 on respiratory tract cells, our work underlines viral epigenetic glycosylation in authentic viral infection and highlights the attachment co-receptor role of DC&L-SIGN in SARS-CoV-2 infection and prevention.
DC&L-SIGN are SARS-CoV-2 attachment co-receptor Viral spike (S) glycoprotein undergoes epigenetic modification during infection Epigenetic glycosylation affects viral in-cis&-trans infections through DC&L-SIGN High-mannose glycan at 1098 site of postfusion S trimer is vital for viral infection
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Affiliation(s)
- Lei Guo
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.,Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming, China
| | - Yan Liang
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Heng Li
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Huiwen Zheng
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Zening Yang
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Yanli Chen
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xin Zhao
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Jing Li
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Binxiang Li
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Haijing Shi
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Ming Sun
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Longding Liu
- Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
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31
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Palacios-Rápalo SN, De Jesús-González LA, Cordero-Rivera CD, Farfan-Morales CN, Osuna-Ramos JF, Martínez-Mier G, Quistián-Galván J, Muñoz-Pérez A, Bernal-Dolores V, del Ángel RM, Reyes-Ruiz JM. Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry. Front Immunol 2021; 12:796855. [PMID: 34975904 PMCID: PMC8719300 DOI: 10.3389/fimmu.2021.796855] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/29/2021] [Indexed: 12/13/2022] Open
Abstract
Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.
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Affiliation(s)
- Selvin Noé Palacios-Rápalo
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Luis Adrián De Jesús-González
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Carlos Daniel Cordero-Rivera
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Carlos Noe Farfan-Morales
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Juan Fidel Osuna-Ramos
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - Gustavo Martínez-Mier
- Unidad Médica de Alta Especialidad, Hospital de Especialidades No. 14, Centro Médico Nacional “Adolfo Ruiz Cortines”, Instituto Mexicano del Seguro Social (IMSS) Veracruz Norte, Veracruz, Mexico
| | - Judith Quistián-Galván
- Unidad Médica de Alta Especialidad, Hospital de Especialidades No. 14, Centro Médico Nacional “Adolfo Ruiz Cortines”, Instituto Mexicano del Seguro Social (IMSS) Veracruz Norte, Veracruz, Mexico
| | - Armando Muñoz-Pérez
- Unidad Médica de Alta Especialidad, Hospital de Especialidades No. 14, Centro Médico Nacional “Adolfo Ruiz Cortines”, Instituto Mexicano del Seguro Social (IMSS) Veracruz Norte, Veracruz, Mexico
| | - Víctor Bernal-Dolores
- Unidad Médica de Alta Especialidad, Hospital de Especialidades No. 14, Centro Médico Nacional “Adolfo Ruiz Cortines”, Instituto Mexicano del Seguro Social (IMSS) Veracruz Norte, Veracruz, Mexico
| | - Rosa María del Ángel
- Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico
| | - José Manuel Reyes-Ruiz
- Unidad Médica de Alta Especialidad, Hospital de Especialidades No. 14, Centro Médico Nacional “Adolfo Ruiz Cortines”, Instituto Mexicano del Seguro Social (IMSS) Veracruz Norte, Veracruz, Mexico
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32
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Xie L, Zhang Z, Wang Q, Chen Y, Lu D, Wu W. COVID-19 and Diabetes: A Comprehensive Review of Angiotensin Converting Enzyme 2, Mutual Effects and Pharmacotherapy. Front Endocrinol (Lausanne) 2021; 12:772865. [PMID: 34867819 PMCID: PMC8639866 DOI: 10.3389/fendo.2021.772865] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 10/29/2021] [Indexed: 01/08/2023] Open
Abstract
The potential relationship between diabetes and COVID-19 has been evaluated. However, new knowledge is rapidly emerging. In this study, we systematically reviewed the relationship between viral cell surface receptors (ACE2, AXL, CD147, DC-SIGN, L-SIGN and DPP4) and SARS-CoV-2 infection risk, and emphasized the implications of ACE2 on SARS-CoV-2 infection and COVID-19 pathogenesis. Besides, we updated on the two-way interactions between diabetes and COVID-19, as well as the treatment options for COVID-19 comorbid patients from the perspective of ACE2. The efficacies of various clinical chemotherapeutic options, including anti-diabetic drugs, renin-angiotensin-aldosterone system inhibitors, lipid-lowering drugs, anticoagulants, and glucocorticoids for COVID-19 positive diabetic patients were discussed. Moreover, we reviewed the significance of two different forms of ACE2 (mACE2 and sACE2) and gender on COVID-19 susceptibility and severity. This review summarizes COVID-19 pathophysiology and the best strategies for clinical management of diabetes patients with COVID-19.
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Affiliation(s)
| | | | | | | | | | - Weihua Wu
- Department of Endocrinology, The 3rd Affiliated Hospital of Shenzhen University, Shenzhen, China
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Bhandari S, Larsen AK, McCourt P, Smedsrød B, Sørensen KK. The Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease. Front Physiol 2021; 12:757469. [PMID: 34707514 PMCID: PMC8542980 DOI: 10.3389/fphys.2021.757469] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively “silenced” by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease.
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Affiliation(s)
- Sabin Bhandari
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Anett Kristin Larsen
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Peter McCourt
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Bård Smedsrød
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Karen Kristine Sørensen
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
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