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1
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Spengler JR, Lo MK, Welch SR, Spiropoulou CF. Henipaviruses: epidemiology, ecology, disease, and the development of vaccines and therapeutics. Clin Microbiol Rev 2025; 38:e0012823. [PMID: 39714175 PMCID: PMC11905374 DOI: 10.1128/cmr.00128-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2024] Open
Abstract
SUMMARYHenipaviruses were first identified 30 years ago and have since been associated with over 30 outbreaks of disease in humans. Highly pathogenic henipaviruses include Hendra virus (HeV) and Nipah virus (NiV), classified as biosafety level 4 pathogens. In addition, NiV has been listed as a priority pathogen by the World Health Organization (WHO), the Coalition for Epidemic Preparedness Innovations (CEPI), and the UK Vaccines Research and Development Network (UKVN). Here, we re-examine epidemiological, ecological, clinical, and pathobiological studies of HeV and NiV to provide a comprehensive guide of the current knowledge and application to identify and evaluate countermeasures. We also discuss therapeutic and vaccine development efforts. Furthermore, with case identification, prevention, and treatment in mind, we highlight limitations in research and recognize gaps necessitating additional studies.
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Affiliation(s)
- Jessica R. Spengler
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Michael K. Lo
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Stephen R. Welch
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Christina F. Spiropoulou
- Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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2
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Rissmann M, Noack D, Spliethof TM, Vaes VP, Stam R, van Run P, Clark JJ, Verjans GMGM, Haagmans BL, Krammer F, Koopmans MPG, van den Brand JMA, Rockx B. A pan-orthohantavirus human lung xenograft mouse model and its utility for preclinical studies. PLoS Pathog 2025; 21:e1012875. [PMID: 39841788 PMCID: PMC11774489 DOI: 10.1371/journal.ppat.1012875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 01/28/2025] [Accepted: 01/01/2025] [Indexed: 01/24/2025] Open
Abstract
Orthohantaviruses are emerging zoonotic viruses that can infect humans via the respiratory tract. There is an unmet need for an in vivo model to study infection of different orthohantaviruses in physiologically relevant tissue and to assess the efficacy of novel pan-orthohantavirus countermeasures. Here, we describe the use of a human lung xenograft mouse model to study the permissiveness for different orthohantavirus species and to assess its utility for preclinical testing of therapeutics. Following infection of xenografted human lung tissues, distinct orthohantavirus species differentially replicated in the human lung and subsequently spread systemically. The different orthohantaviruses primarily targeted the endothelium, respiratory epithelium and macrophages in the human lung. A proof-of-concept preclinical study showed treatment of these mice with a virus neutralizing antibody could block Andes orthohantavirus infection and dissemination. This pan-orthohantavirus model will facilitate progress in the fundamental understanding of pathogenesis and virus-host interactions for orthohantaviruses. Furthermore, it is an invaluable tool for preclinical evaluation of novel candidate pan-orthohantavirus intervention strategies.
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Affiliation(s)
- Melanie Rissmann
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Danny Noack
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Thomas M. Spliethof
- Division of Pathology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Vincent P. Vaes
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Rianne Stam
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Peter van Run
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jordan J. Clark
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | | | - Bart L. Haagmans
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Florian Krammer
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Marion P. G. Koopmans
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
| | | | - Barry Rockx
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands
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Wang S, Li W, Wang Z, Yang W, Li E, Xia X, Yan F, Chiu S. Emerging and reemerging infectious diseases: global trends and new strategies for their prevention and control. Signal Transduct Target Ther 2024; 9:223. [PMID: 39256346 PMCID: PMC11412324 DOI: 10.1038/s41392-024-01917-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 06/13/2024] [Accepted: 07/05/2024] [Indexed: 09/12/2024] Open
Abstract
To adequately prepare for potential hazards caused by emerging and reemerging infectious diseases, the WHO has issued a list of high-priority pathogens that are likely to cause future outbreaks and for which research and development (R&D) efforts are dedicated, known as paramount R&D blueprints. Within R&D efforts, the goal is to obtain effective prophylactic and therapeutic approaches, which depends on a comprehensive knowledge of the etiology, epidemiology, and pathogenesis of these diseases. In this process, the accessibility of animal models is a priority bottleneck because it plays a key role in bridging the gap between in-depth understanding and control efforts for infectious diseases. Here, we reviewed preclinical animal models for high priority disease in terms of their ability to simulate human infections, including both natural susceptibility models, artificially engineered models, and surrogate models. In addition, we have thoroughly reviewed the current landscape of vaccines, antibodies, and small molecule drugs, particularly hopeful candidates in the advanced stages of these infectious diseases. More importantly, focusing on global trends and novel technologies, several aspects of the prevention and control of infectious disease were discussed in detail, including but not limited to gaps in currently available animal models and medical responses, better immune correlates of protection established in animal models and humans, further understanding of disease mechanisms, and the role of artificial intelligence in guiding or supplementing the development of animal models, vaccines, and drugs. Overall, this review described pioneering approaches and sophisticated techniques involved in the study of the epidemiology, pathogenesis, prevention, and clinical theatment of WHO high-priority pathogens and proposed potential directions. Technological advances in these aspects would consolidate the line of defense, thus ensuring a timely response to WHO high priority pathogens.
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Affiliation(s)
- Shen Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, China
| | - Wujian Li
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, China
- College of Veterinary Medicine, Jilin University, Changchun, Jilin, China
| | - Zhenshan Wang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, China
- College of Veterinary Medicine, Jilin Agricultural University, Changchun, Jilin, China
| | - Wanying Yang
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, China
| | - Entao Li
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China
- Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, 230027, Anhui, China
| | - Xianzhu Xia
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, China
| | - Feihu Yan
- Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, China.
| | - Sandra Chiu
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, Anhui, China.
- Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, 230027, Anhui, China.
- Department of Laboratory Medicine, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
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Pigeaud DD, Geisbert TW, Woolsey C. Animal Models for Henipavirus Research. Viruses 2023; 15:1980. [PMID: 37896758 PMCID: PMC10610982 DOI: 10.3390/v15101980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Hendra virus (HeV) and Nipah virus (NiV) are zoonotic paramyxoviruses in the genus Henipavirus (HNV) that emerged nearly thirty years ago. Outbreaks of HeV and NiV have led to severe respiratory disease and encephalitis in humans and animals characterized by a high mortality rate. Despite the grave threat HNVs pose to public health and global biosecurity, no approved medical countermeasures for human use currently exist against HeV or NiV. To develop candidate vaccines and therapeutics and advance the field's understanding of HNV pathogenesis, animal models of HeV and NiV have been instrumental and remain indispensable. Various species, including rodents, ferrets, and nonhuman primates (NHPs), have been employed for HNV investigations. Among these, NHPs have demonstrated the closest resemblance to human HNV disease, although other animal models replicate some key disease features. Here, we provide a comprehensive review of the currently available animal models (mice, hamsters, guinea pigs, ferrets, cats, dogs, nonhuman primates, horses, and swine) to support HNV research. We also discuss the strengths and limitations of each model for conducting pathogenesis and transmission studies on HeV and NiV and for the evaluation of medical countermeasures.
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Affiliation(s)
- Declan D. Pigeaud
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA; (D.D.P.); (T.W.G.)
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Thomas W. Geisbert
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA; (D.D.P.); (T.W.G.)
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Courtney Woolsey
- Galveston National Laboratory, University of Texas Medical Branch, Galveston, TX 77555, USA; (D.D.P.); (T.W.G.)
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
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Ivanova T, Mariienko Y, Mehterov N, Kazakova M, Sbirkov Y, Todorova K, Hayrabedyan S, Sarafian V. Autophagy and SARS-CoV-2-Old Players in New Games. Int J Mol Sci 2023; 24:7734. [PMID: 37175443 PMCID: PMC10178552 DOI: 10.3390/ijms24097734] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
At present it is well-defined that autophagy is a fundamental process essential for cell life but its pro-viral and anti-viral role has been stated out with the COVID pandemic. However, viruses in turn have evolved diverse adaptive strategies to cope with autophagy driven host defense, either by blocking or hijacking the autophagy machinery for their own benefit. The mechanisms underlying autophagy modulation are presented in the current review which summarizes the accumulated knowledge on the crosstalk between autophagy and viral infections, with a particular emphasizes on SARS-CoV-2. The different types of autophagy related to infections and their molecular mechanisms are focused in the context of inflammation. In particular, SARS-CoV-2 entry, replication and disease pathogenesis are discussed. Models to study autophagy and to formulate novel treatment approaches and pharmacological modulation to fight COVID-19 are debated. The SARS-CoV-2-autophagy interplay is presented, revealing the complex dynamics and the molecular machinery of autophagy. The new molecular targets and strategies to treat COVID-19 effectively are envisaged. In conclusion, our finding underline the importance of development new treatment strategies and pharmacological modulation of autophagy to fight COVID-19.
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Affiliation(s)
- Tsvetomira Ivanova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Yuliia Mariienko
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Nikolay Mehterov
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Maria Kazakova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Yordan Sbirkov
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Krassimira Todorova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Soren Hayrabedyan
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
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Zhang C, Wei B, Liu Z, Yao W, Li Y, Lu J, Ge C, Yu X, Li D, Zhu Y, Shang C, Jin N, Li X. Bafilomycin A1 inhibits SARS-CoV-2 infection in a human lung xenograft mouse model. Virol J 2023; 20:18. [PMID: 36721152 PMCID: PMC9887234 DOI: 10.1186/s12985-023-01971-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 01/10/2023] [Indexed: 02/01/2023] Open
Abstract
Coronavirus disease 2019 is a global pandemic caused by SARS-CoV-2. The emergence of its variant strains has posed a considerable challenge to clinical treatment. Therefore, drugs capable of inhibiting SARS-CoV-2 infection, regardless of virus variations, are in urgently need. Our results showed that the endosomal acidification inhibitor, Bafilomycin A1 (Baf-A1), had an inhibitory effect on the viral RNA synthesis of SARS-CoV-2, and its Beta and Delta variants at the concentration of 500 nM. Moreover, the human lung xenograft mouse model was used to investigate the anti-SARS-CoV-2 effect of Baf-A1. It was found that Baf-A1 significantly inhibited SARS-CoV-2 replication in the human lung xenografts by in situ hybridization and RT-PCR assays. Histopathological examination showed that Baf-A1 alleviated SARS-CoV-2-induced diffuse inflammatory infiltration of granulocytes and macrophages and alveolar endothelial cell death in human lung xenografts. In addition, immunohistochemistry analysis indicated that Baf-A1 decreased inflammatory exudation and infiltration in SARS-CoV-2-infected human lung xenografts. Therefore, Baf-A1 may be a candidate drug for SARS-CoV-2 treatment.
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Affiliation(s)
- Cuiling Zhang
- grid.410727.70000 0001 0526 1937Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122 Jilin People’s Republic of China
| | - Bingjie Wei
- grid.144022.10000 0004 1760 4150Veterinary Medicine College, Northwest A&F University, Shaanxi, 712100 People’s Republic of China
| | - Zirui Liu
- grid.410727.70000 0001 0526 1937Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122 Jilin People’s Republic of China
| | - Wei Yao
- Healthcare Department, Agency for Offices Administration, 23 Xinwai Street, Haidian District, Beijing, 100082 People’s Republic of China
| | - Yiquan Li
- grid.440665.50000 0004 1757 641XChangchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Jing Lu
- grid.410727.70000 0001 0526 1937Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122 Jilin People’s Republic of China
| | - Chenchen Ge
- grid.410727.70000 0001 0526 1937Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122 Jilin People’s Republic of China
| | - Xiaoyang Yu
- grid.410727.70000 0001 0526 1937Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122 Jilin People’s Republic of China
| | - Dapeng Li
- grid.410727.70000 0001 0526 1937Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122 Jilin People’s Republic of China
| | - Yilong Zhu
- Changchun University of Chinese Medicine, Changchun, People's Republic of China.
| | - Chao Shang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122, Jilin, People's Republic of China.
| | - Ningyi Jin
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122, Jilin, People's Republic of China. .,Changchun University of Chinese Medicine, Changchun, People's Republic of China. .,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China.
| | - Xiao Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Yujinxiang road, 573, Jingyue Economic and Technological Development Zone, Changchun, 130122, Jilin, People's Republic of China. .,Changchun University of Chinese Medicine, Changchun, People's Republic of China. .,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People's Republic of China.
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Valbuena G, Rockx B, Escaffre O. Generation and Characterization of a Humanized Lung Xenograft Mouse Model for Studying Henipavirus Pathogenesis. Methods Mol Biol 2023; 2682:191-204. [PMID: 37610583 DOI: 10.1007/978-1-0716-3283-3_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
The development of humanized mouse models has recently opened new avenues in the field of infectious diseases. These models allow research on many human viruses that were once difficult to study, because finding suitable animal models of infection can be challenging, cost prohibitive, and often do not entirely recapitulate all parameters of the disease. Here, we describe the procedure of human immune system reconstitution (humanization) of NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice by the bone marrow, liver, and thymus (BLT) reconstitution method as well as the process of human lung engraftment. We then describe how to infect these human lung grafts with the paramyxovirus Nipah virus (NiV) that can cause lethal respiratory disease in humans, and for which there is only limited understanding of pathogenesis to acute lung injury.
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Affiliation(s)
| | - Barry Rockx
- Wageningen Bioveterinary Institute, Lelystad and Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Olivier Escaffre
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
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Liew YJM, Ibrahim PAS, Ong HM, Chong CN, Tan CT, Schee JP, Gómez Román R, Cherian NG, Wong WF, Chang LY. The Immunobiology of Nipah Virus. Microorganisms 2022; 10:microorganisms10061162. [PMID: 35744680 PMCID: PMC9228579 DOI: 10.3390/microorganisms10061162] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 12/23/2022] Open
Abstract
Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that emerged in Malaysia in 1998. It is a human pathogen capable of causing severe respiratory infection and encephalitis. The natural reservoir of NiV, Pteropus fruit bats, remains a continuous virus source for future outbreaks, although infection in the bats is largely asymptomatic. NiV provokes serious disease in various mammalian species. In the recent human NiV outbreaks in Bangladesh and India, both bats-to-human and human-to-human transmissions have been observed. NiV has been demonstrated to interfere with the innate immune response via interferon type I signaling, promoting viral dissemination and preventing antiviral response. Studies of humoral immunity in infected NiV patients and animal models have shown that NiV-specific antibodies were produced upon infection and were protective. Studies on cellular immunity response to NiV infection in human and animal models also found that the adaptive immune response, specifically CD4+ and CD8+ T cells, was stimulated upon NiV infection. The experimental vaccines and therapeutic strategies developed have provided insights into the immunological requirements for the development of successful medical countermeasures against NiV. This review summarizes the current understanding of NiV pathogenesis and innate and adaptive immune responses induced upon infection.
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Affiliation(s)
- Yvonne Jing Mei Liew
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (Y.J.M.L.); (P.A.S.I.); (H.M.O.); (C.N.C.); (W.F.W.)
- Deputy Vice Chancellor’s Office (Research & Innovation), Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Puteri Ainaa S. Ibrahim
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (Y.J.M.L.); (P.A.S.I.); (H.M.O.); (C.N.C.); (W.F.W.)
| | - Hui Ming Ong
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (Y.J.M.L.); (P.A.S.I.); (H.M.O.); (C.N.C.); (W.F.W.)
| | - Chee Ning Chong
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (Y.J.M.L.); (P.A.S.I.); (H.M.O.); (C.N.C.); (W.F.W.)
| | - Chong Tin Tan
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.T.T.); (J.P.S.)
| | - Jie Ping Schee
- Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.T.T.); (J.P.S.)
| | - Raúl Gómez Román
- Vaccine Research and Development, Coalition for Epidemic Preparedness Innovation (CEPI), Askekroken 11, 0277 Oslo, Norway; (R.G.R.); (N.G.C.)
| | - Neil George Cherian
- Vaccine Research and Development, Coalition for Epidemic Preparedness Innovation (CEPI), Askekroken 11, 0277 Oslo, Norway; (R.G.R.); (N.G.C.)
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (Y.J.M.L.); (P.A.S.I.); (H.M.O.); (C.N.C.); (W.F.W.)
| | - Li-Yen Chang
- Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (Y.J.M.L.); (P.A.S.I.); (H.M.O.); (C.N.C.); (W.F.W.)
- Correspondence:
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9
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Lawrence P, Escudero-Pérez B. Henipavirus Immune Evasion and Pathogenesis Mechanisms: Lessons Learnt from Natural Infection and Animal Models. Viruses 2022; 14:v14050936. [PMID: 35632678 PMCID: PMC9146692 DOI: 10.3390/v14050936] [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: 03/22/2022] [Revised: 04/27/2022] [Accepted: 04/27/2022] [Indexed: 02/01/2023] Open
Abstract
Nipah henipavirus (NiV) and Hendra henipavirus (HeV) are zoonotic emerging paramyxoviruses causing severe disease outbreaks in humans and livestock, mostly in Australia, India, Malaysia, Singapore and Bangladesh. Both are bat-borne viruses and in humans, their mortality rates can reach 60% in the case of HeV and 92% for NiV, thus being two of the deadliest viruses known for humans. Several factors, including a large cellular tropism and a wide zoonotic potential, con-tribute to their high pathogenicity. This review provides an overview of HeV and NiV pathogenicity mechanisms and provides a summary of their interactions with the immune systems of their different host species, including their natural hosts bats, spillover-hosts pigs, horses, and humans, as well as in experimental animal models. A better understanding of the interactions between henipaviruses and their hosts could facilitate the development of new therapeutic strategies and vaccine measures against these re-emerging viruses.
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Affiliation(s)
- Philip Lawrence
- Science and Humanities Confluence Research Centre (EA 1598), Catholic University of Lyon (UCLy), 69002 Lyon, France
- Correspondence: (P.L.); (B.E.-P.)
| | - Beatriz Escudero-Pérez
- WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany
- German Centre for Infection Research (DZIF), Partner Site Hamburg-Luebeck-Borstel, 38124 Braunschweig, Germany
- Correspondence: (P.L.); (B.E.-P.)
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10
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Liu J, Yao L, Huang S, Wang B, Li L, Li L, Gu W, Xiao S, Liu G. AMG487 inhibits PRRSV replication and ameliorates lung injury in pig lung xenografts by down-regulating the expression of ANXA2. Antiviral Res 2022; 202:105314. [DOI: 10.1016/j.antiviral.2022.105314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/25/2022] [Accepted: 04/01/2022] [Indexed: 12/25/2022]
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Li YR, Dunn ZS, Garcia G, Carmona C, Zhou Y, Lee D, Yu J, Huang J, Kim JT, Arumugaswami V, Wang P, Yang L. Development of off-the-shelf hematopoietic stem cell-engineered invariant natural killer T cells for COVID-19 therapeutic intervention. Stem Cell Res Ther 2022; 13:112. [PMID: 35313965 PMCID: PMC8935266 DOI: 10.1186/s13287-022-02787-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/16/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND New COVID-19 treatments are desperately needed as case numbers continue to rise and emergent strains threaten vaccine efficacy. Cell therapy has revolutionized cancer treatment and holds much promise in combatting infectious disease, including COVID-19. Invariant natural killer T (iNKT) cells are a rare subset of T cells with potent antiviral and immunoregulatory functions and an excellent safety profile. Current iNKT cell strategies are hindered by the extremely low presence of iNKT cells, and we have developed a platform to overcome this critical limitation. METHODS We produced allogeneic HSC-engineered iNKT (AlloHSC-iNKT) cells through TCR engineering of human cord blood CD34+ hematopoietic stem cells (HSCs) and differentiation of these HSCs into iNKT cells in an Ex Vivo HSC-Derived iNKT Cell Culture. We then established in vitro SARS-CoV-2 infection assays to assess AlloHSC-iNKT cell antiviral and anti-hyperinflammation functions. Lastly, using in vitro and in vivo preclinical models, we evaluated AlloHSC-iNKT cell safety and immunogenicity for off-the-shelf application. RESULTS We reliably generated AlloHSC-iNKT cells at high-yield and of high-purity; these resulting cells closely resembled endogenous human iNKT cells in phenotypes and functionalities. In cell culture, AlloHSC-iNKT cells directly killed SARS-CoV-2 infected cells and also selectively eliminated SARS-CoV-2 infection-stimulated inflammatory monocytes. In an in vitro mixed lymphocyte reaction (MLR) assay and an NSG mouse xenograft model, AlloHSC-iNKT cells were resistant to T cell-mediated alloreaction and did not cause GvHD. CONCLUSIONS Here, we report a method to robustly produce therapeutic levels of AlloHSC-iNKT cells. Preclinical studies showed that these AlloHSC-iNKT cells closely resembled endogenous human iNKT cells, could reduce SARS-CoV-2 virus infection load and mitigate virus infection-induced hyperinflammation, and meanwhile were free of GvHD-risk and resistant to T cell-mediated allorejection. These results support the development of AlloHSC-iNKT cells as a promising off-the-shelf cell product for treating COVID-19; such a cell product has the potential to target the new emerging SARS-CoV-2 variants as well as the future new emerging viruses.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Zachary Spencer Dunn
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, Los Angeles, CA, 90089, USA
| | - Gustavo Garcia
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Camille Carmona
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Yang Zhou
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Derek Lee
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Jiaji Yu
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Jie Huang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Jocelyn T Kim
- Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Vaithilingaraja Arumugaswami
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - Pin Wang
- Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, Los Angeles, CA, 90089, USA
| | - Lili Yang
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
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12
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Wang Y, Wang L, Fu C, Wang X, Zuo S, Shu C, Shan Y, He J, Zhou Q, Li W, Yang YG, Hu Z, Hua S. Exploration of Human Lung-Resident Immunity and Response to Respiratory Viral Immunization in a Humanized Mouse Model. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:420-428. [PMID: 34903640 DOI: 10.4049/jimmunol.2100122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 11/04/2021] [Indexed: 06/14/2023]
Abstract
There are urgent needs for humanized mouse models of viral respiratory diseases to study immunopathogenesis and therapeutic interventions. Although human immune system (HIS) mice permit analysis in real time of human immune responses in vivo, evolutionary divergences preclude their usefulness for the respiratory viruses that do not infect mouse lungs. In this study, we sought to use HIS mice with human lung (HL) tissue xenografts (HISL mice) to address this issue. The grafted HL tissue maintained histologically normal structure, and populated with human tissue-resident immune cells, including CD11c+ dendritic cells and CD4+ and CD8+ tissue-resident memory T cells. HISL mice showed a marked expansion of tissue-resident memory T cells and generation of viral Ag-specific T cells in the HL xenografts, and production of antiviral IgM and IgG Abs upon immunization of the HL xenograft by H1N1 influenza viruses. RNA-seq analysis on H1N1-infected and control HL xenografts identified a total of 5089 differentially expressed genes with enrichments for genes involved in respiratory diseases, viral infections, and associated immune responses. Furthermore, prophylactic viral exposures resulted in protection against subsequent lethal challenge by intranasal viral inoculation. This study supports the usefulness of this preclinical model in exploring the immunopathology and therapies of respiratory viral diseases.
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Affiliation(s)
- Yixin Wang
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Lei Wang
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Cong Fu
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Xue Wang
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Siyao Zuo
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Chang Shu
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Yanhong Shan
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Jin He
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; and
| | - Wei Li
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; and
| | - Yong-Guang Yang
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China;
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Zheng Hu
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China;
- National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, China
| | - Shucheng Hua
- Department of Respiration, Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, The First Hospital of Jilin University, Changchun, China;
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13
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Gabra MD, Ghaith HS, Ebada MA. Nipah Virus: An Updated Review and Emerging Challenges. Infect Disord Drug Targets 2022; 22:e170122200296. [PMID: 35078400 DOI: 10.2174/1871526522666220117120859] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/17/2021] [Accepted: 12/02/2021] [Indexed: 06/14/2023]
Abstract
Many hospitals are teetering on the edge of being overwhelmed, with many already there because of the COVID-19 pandemic. Moreover, a recent report has also warned about the Nipah virus (NiV). NiV is a pleomorphic enveloped virus that belongs to the Paramyxoviridae family (genus Henipavirus); it affects both the respiratory and central nervous systems, with a fatality rate ranging from 40% to 75%, as documented by the World Health Organization. The first reported NiV outbreak was in early 1999 in Malaysia among people who contacted infected pigs. NiV also affected Bangladesh and India, where the main infection route was the consumption of raw date palm sap contaminated by bats. The World Health Organization has listed NiV as one of the emerging pathogens that can lead to severe outbreaks at any moment in the future with limited medical preparations and only a few projects in pharmaceutical firms. There is no licensed treatment for human use against NiV until now, and the management is limited to supportive care and symptomatic treatment. In severe cases with neurologic and respiratory complications, intensive care is needed. This article reviews the published literature and highlights the latest updates about this emerging pathogen and the methods to avoid the spread of this disease during this critical period.
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Affiliation(s)
| | | | - Mahmoud Ahmed Ebada
- Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt
- Internal Medicine Resident, Ministry of Health and Population of Egypt, Cairo, Egypt
- Department of Internal Medicine and Endocrinology, National Institute of Diabetes and Endocrinology (NIDE), Cairo, Egypt
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14
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Shang C, Zhuang X, Zhang H, Li Y, Zhu Y, Lu J, Ge C, Cong J, Li T, Li N, Tian M, Jin N, Li X. Inhibition of Autophagy Suppresses SARS-CoV-2 Replication and Ameliorates Pneumonia in hACE2 Transgenic Mice and Xenografted Human Lung Tissues. J Virol 2021; 95:e0153721. [PMID: 34550769 PMCID: PMC8610582 DOI: 10.1128/jvi.01537-21] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/17/2021] [Indexed: 01/08/2023] Open
Abstract
Autophagy is thought to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, how SARS-CoV-2 interferes with the autophagic pathway and whether autophagy contributes to virus infection in vivo is unclear. In this study, we identified SARS-CoV-2-triggered autophagy in animal models, including the long-tailed or crab-eating macaque (Macaca fascicularis), human angiotensin-converting enzyme 2 (hACE2) transgenic mice, and xenografted human lung tissues. In Vero E6 and Huh-7 cells, SARS-CoV-2 induces autophagosome formation, accompanied by consistent autophagic events, including inhibition of the Akt-mTOR pathway and activation of the ULK-1-Atg13 and VPS34-VPS15-Beclin1 complexes, but it blocks autophagosome-lysosome fusion. Modulation of autophagic elements, including the VPS34 complex and Atg14, but not Atg5, inhibits SARS-CoV-2 replication. Moreover, this study represents the first to demonstrate that the mouse bearing xenografted human lung tissue is a suitable model for SARS-CoV-2 infection and that autophagy inhibition suppresses SARS-CoV-2 replication and ameliorates virus-associated pneumonia in human lung tissues. We also observed a critical role of autophagy in SARS-CoV-2 infection in an hACE2 transgenic mouse model. This study, therefore, gives insights into the mechanisms by which SARS-CoV-2 manipulates autophagosome formation, and we suggest that autophagy-inhibiting agents might be useful as therapeutic agents against SARS-CoV-2 infection. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with limited therapeutics. Insights into the virus-host interactions contribute substantially to the development of anti-SARS-CoV-2 therapeutics. The novelty of this study is the use of a new animal model: mice xenografted with human lung tissues. Using a combination of in vitro and in vivo studies, we have obtained experimental evidence that induction of autophagy contributes to SARS-CoV-2 infection and improves our understanding of potential therapeutic targets for SARS-CoV-2.
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Affiliation(s)
- Chao Shang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| | - Xinyu Zhuang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| | - He Zhang
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| | - Yiquan Li
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Yilong Zhu
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Jing Lu
- Agricultural College, Yanbian University, Yanji, People’s Republic of China
| | - Chenchen Ge
- Agricultural College, Yanbian University, Yanji, People’s Republic of China
| | - Jianan Cong
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Tingyu Li
- Agricultural College, Yanbian University, Yanji, People’s Republic of China
| | - Nan Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| | - Mingyao Tian
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| | - Ningyi Jin
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People’s Republic of China
| | - Xiao Li
- Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, People’s Republic of China
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15
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Gamble A, Yeo YY, Butler AA, Tang H, Snedden CE, Mason CT, Buchholz DW, Bingham J, Aguilar HC, Lloyd-Smith JO. Drivers and Distribution of Henipavirus-Induced Syncytia: What Do We Know? Viruses 2021; 13:1755. [PMID: 34578336 PMCID: PMC8472861 DOI: 10.3390/v13091755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/21/2021] [Accepted: 08/25/2021] [Indexed: 12/20/2022] Open
Abstract
Syncytium formation, i.e., cell-cell fusion resulting in the formation of multinucleated cells, is a hallmark of infection by paramyxoviruses and other pathogenic viruses. This natural mechanism has historically been a diagnostic marker for paramyxovirus infection in vivo and is now widely used for the study of virus-induced membrane fusion in vitro. However, the role of syncytium formation in within-host dissemination and pathogenicity of viruses remains poorly understood. The diversity of henipaviruses and their wide host range and tissue tropism make them particularly appropriate models with which to characterize the drivers of syncytium formation and the implications for virus fitness and pathogenicity. Based on the henipavirus literature, we summarized current knowledge on the mechanisms driving syncytium formation, mostly acquired from in vitro studies, and on the in vivo distribution of syncytia. While these data suggest that syncytium formation widely occurs across henipaviruses, hosts, and tissues, we identified important data gaps that undermined our understanding of the role of syncytium formation in virus pathogenesis. Based on these observations, we propose solutions of varying complexity to fill these data gaps, from better practices in data archiving and publication for in vivo studies, to experimental approaches in vitro.
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Affiliation(s)
- Amandine Gamble
- Department of Ecology & Evolutionary Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.A.B.); (H.T.); (C.E.S.); (J.O.L.-S.)
| | - Yao Yu Yeo
- Department of Microbiology & Immunology, Cornell University, Ithaca, NY 14850, USA; (Y.Y.Y.); (D.W.B.); (H.C.A.)
| | - Aubrey A. Butler
- Department of Ecology & Evolutionary Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.A.B.); (H.T.); (C.E.S.); (J.O.L.-S.)
| | - Hubert Tang
- Department of Ecology & Evolutionary Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.A.B.); (H.T.); (C.E.S.); (J.O.L.-S.)
| | - Celine E. Snedden
- Department of Ecology & Evolutionary Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.A.B.); (H.T.); (C.E.S.); (J.O.L.-S.)
| | - Christian T. Mason
- Department of Computational Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA;
| | - David W. Buchholz
- Department of Microbiology & Immunology, Cornell University, Ithaca, NY 14850, USA; (Y.Y.Y.); (D.W.B.); (H.C.A.)
| | - John Bingham
- CSIRO Australian Centre for Disease Preparedness, Geelong, VIC 3220, Australia;
| | - Hector C. Aguilar
- Department of Microbiology & Immunology, Cornell University, Ithaca, NY 14850, USA; (Y.Y.Y.); (D.W.B.); (H.C.A.)
| | - James O. Lloyd-Smith
- Department of Ecology & Evolutionary Biology, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.A.B.); (H.T.); (C.E.S.); (J.O.L.-S.)
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16
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Dash PK, Gorantla S, Poluektova L, Hasan M, Waight E, Zhang C, Markovic M, Edagwa B, Machhi J, Olson KE, Wang X, Mosley RL, Kevadiya B, Gendelman HE. Humanized Mice for Infectious and Neurodegenerative disorders. Retrovirology 2021; 18:13. [PMID: 34090462 PMCID: PMC8179712 DOI: 10.1186/s12977-021-00557-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 05/22/2021] [Indexed: 12/12/2022] Open
Abstract
Humanized mice model human disease and as such are used commonly for research studies of infectious, degenerative and cancer disorders. Recent models also reflect hematopoiesis, natural immunity, neurobiology, and molecular pathways that influence disease pathobiology. A spectrum of immunodeficient mouse strains permit long-lived human progenitor cell engraftments. The presence of both innate and adaptive immunity enables high levels of human hematolymphoid reconstitution with cell susceptibility to a broad range of microbial infections. These mice also facilitate investigations of human pathobiology, natural disease processes and therapeutic efficacy in a broad spectrum of human disorders. However, a bridge between humans and mice requires a complete understanding of pathogen dose, co-morbidities, disease progression, environment, and genetics which can be mirrored in these mice. These must be considered for understanding of microbial susceptibility, prevention, and disease progression. With known common limitations for access to human tissues, evaluation of metabolic and physiological changes and limitations in large animal numbers, studies in mice prove important in planning human clinical trials. To these ends, this review serves to outline how humanized mice can be used in viral and pharmacologic research emphasizing both current and future studies of viral and neurodegenerative diseases. In all, humanized mouse provides cost-effective, high throughput studies of infection or degeneration in natural pathogen host cells, and the ability to test transmission and eradication of disease.
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Affiliation(s)
- Prasanta K Dash
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Santhi Gorantla
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Larisa Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mahmudul Hasan
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Emiko Waight
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Chen Zhang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Milica Markovic
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Benson Edagwa
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Jatin Machhi
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Katherine E Olson
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Xinglong Wang
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - R Lee Mosley
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Bhavesh Kevadiya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Howard E Gendelman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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17
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Fu W, Wang W, Yuan L, Lin Y, Huang X, Chen R, Cai M, Liu C, Chen L, Zhou M, Wu K, Zhao H, Pan D, Ma J, Hong J, Zhai B, Zhang Y, Kong Z, Wang Y, Chen Y, Yuan Q, Zhu H, Cheng T, Guan Y, Xia N. A SCID mouse-human lung xenograft model of SARS-CoV-2 infection. Theranostics 2021; 11:6607-6615. [PMID: 33995679 PMCID: PMC8120224 DOI: 10.7150/thno.58321] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/07/2021] [Indexed: 12/13/2022] Open
Abstract
SARS-CoV-2 infection, which is responsible for the current COVID-19 pandemic, can cause life-threatening pneumonia, respiratory failure and even death. Characterizing SARS-CoV-2 pathogenesis in primary human target cells and tissues is crucial for developing vaccines and therapeutics. However, given the limited access to clinical samples from COVID-19 patients, there is a pressing need for in vitro/in vivo models to investigate authentic SARS-CoV-2 infection in primary human lung cells or tissues with mature structures. The present study was designed to evaluate a humanized mouse model carrying human lung xenografts for SARS-CoV-2 infection in vivo. Methods: Human fetal lung tissue surgically grafted under the dorsal skin of SCID mice were assessed for growth and development after 8 weeks. Following SARS-CoV-2 inoculation into the differentiated lung xenografts, viral replication, cell-type tropism and histopathology of SARS-CoV-2 infection, and local cytokine/chemokine expression were determined over a 6-day period. The effect of IFN-α treatment against SARS-CoV-2 infection was tested in the lung xenografts. Results: Human lung xenografts expanded and developed mature structures closely resembling normal human lung. SARS-CoV-2 replicated and spread efficiently in the lung xenografts with the epithelial cells as the main target, caused severe lung damage, and induced a robust pro-inflammatory response. IFN-α treatment effectively inhibited SARS-CoV-2 replication in the lung xenografts. Conclusions: These data support the human lung xenograft mouse model as a useful and biological relevant tool that should facilitate studies on the pathogenesis of SARS-CoV-2 lung infection and the evaluation of potential antiviral therapies.
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Affiliation(s)
- Wenkun Fu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Wei Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Lunzhi Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Yanzhen Lin
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Xiamen University, Xiamen 361004, P. R. China
| | - Xiumin Huang
- Department of Obstetrics and Gynecology, Zhongshan Hospital, Xiamen University, Xiamen 361004, P. R. China
| | - Rirong Chen
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, P. R. China
- Joint Institute of Virology (Shantou University and The University of Hong Kong), Guangdong-Hongkong Joint Laboratory of Emerging Infectious Diseases, Shantou University, Shantou, P. R. China
| | - Minping Cai
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, P. R. China
- Joint Institute of Virology (Shantou University and The University of Hong Kong), Guangdong-Hongkong Joint Laboratory of Emerging Infectious Diseases, Shantou University, Shantou, P. R. China
| | - Che Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Liqiang Chen
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, P. R. China
- Joint Institute of Virology (Shantou University and The University of Hong Kong), Guangdong-Hongkong Joint Laboratory of Emerging Infectious Diseases, Shantou University, Shantou, P. R. China
| | - Ming Zhou
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Kun Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Huan Zhao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Dequan Pan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Jian Ma
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Junping Hong
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Bingke Zhai
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Yali Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Zhibo Kong
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Yingbin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Yixin Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Quan Yuan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Huachen Zhu
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, P. R. China
- Joint Institute of Virology (Shantou University and The University of Hong Kong), Guangdong-Hongkong Joint Laboratory of Emerging Infectious Diseases, Shantou University, Shantou, P. R. China
| | - Tong Cheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
| | - Yi Guan
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, P. R. China
- Joint Institute of Virology (Shantou University and The University of Hong Kong), Guangdong-Hongkong Joint Laboratory of Emerging Infectious Diseases, Shantou University, Shantou, P. R. China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, Fujian, P. R. China
- Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, Xiamen 361102, Fujian, P. R. China
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18
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Nanotechnology-based approaches for emerging and re-emerging viruses: Special emphasis on COVID-19. Microb Pathog 2021; 156:104908. [PMID: 33932543 PMCID: PMC8079947 DOI: 10.1016/j.micpath.2021.104908] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/17/2021] [Accepted: 04/19/2021] [Indexed: 12/17/2022]
Abstract
In recent decades, the major concern of emerging and re-emerging viral diseases has become an increasingly important area of public health concern, and it is of significance to anticipate future pandemic that would inevitably threaten human lives. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged virus that causes mild to severe pneumonia. Coronavirus disease (COVID-19) became a very much concerned issue worldwide after its super-spread across the globe and emerging viral diseases have not got specific and reliable diagnostic and treatments. As the COVID-19 pandemic brings about a massive life-loss across the globe, there is an unmet need to discover a promising and typically effective diagnosis and treatment to prevent super-spreading and mortality from being decreased or even eliminated. This study was carried out to overview nanotechnology-based diagnostic and treatment approaches for emerging and re-emerging viruses with the current treatment of the disease and shed light on nanotechnology's remarkable potential to provide more effective treatment and prevention to a special focus on recently emerged coronavirus.
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19
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Wong JJ, Chen Z, Chung JK, Groves JT, Jardetzky TS. EphrinB2 clustering by Nipah virus G is required to activate and trap F intermediates at supported lipid bilayer-cell interfaces. SCIENCE ADVANCES 2021; 7:eabe1235. [PMID: 33571127 PMCID: PMC7840137 DOI: 10.1126/sciadv.abe1235] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 12/07/2020] [Indexed: 06/12/2023]
Abstract
Paramyxovirus membrane fusion requires an attachment protein that binds to a host cell receptor and a fusion protein that merges the viral and host membranes. For Nipah virus (NiV), the G attachment protein binds ephrinB2/B3 receptors and activates F-mediated fusion. To visualize dynamic events of these proteins at the membrane interface, we reconstituted NiV fusion activation by overlaying F- and G-expressing cells onto ephrinB2-functionalized supported lipid bilayers and used TIRF microscopy to follow F, G, and ephrinB2. We found that G and ephrinB2 form clusters and that oligomerization of ephrinB2 is necessary for F activation. Single-molecule tracking of F particles revealed accumulation of an immobilized intermediate upon activation. We found no evidence for stable F-G protein complexes before or after activation. These observations lead to a revised model for NiV fusion activation and provide a foundation for investigating other multicomponent viral fusion systems.
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Affiliation(s)
- Joyce J Wong
- Department of Structural Biology, Stanford University, Stanford, CA, USA
| | - Zhongwen Chen
- Multiscale Research Institute of Complex Systems, Fudan University, Shanghai, China
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
| | - Jean K Chung
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA
| | - Jay T Groves
- Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA.
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20
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Escudero-Pérez B, Ruibal P, Rottstegge M, Lüdtke A, Port JR, Hartmann K, Gómez-Medina S, Müller-Guhl J, Nelson EV, Krasemann S, Rodríguez E, Muñoz-Fontela C. Comparative pathogenesis of Ebola virus and Reston virus infection in humanized mice. JCI Insight 2019; 4:126070. [PMID: 31550241 PMCID: PMC6948759 DOI: 10.1172/jci.insight.126070] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 09/19/2019] [Indexed: 01/14/2023] Open
Abstract
Filoviruses of the genus Ebolavirus include 6 species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case fatality rates can range between 0% and 90%. In order to understand the molecular basis of these differences, it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Nonhuman primates (NHPs) are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHPs. Here we used HLA-A2-transgenic, NOD-scid-IL-2γ receptor-knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While markedly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, the case fatality ratios of different Ebolavirus species in humans were recapitulated in the humanized mice. Our findings point to humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and suggest that further investigations on Reston virus pathogenesis in humans are warranted.
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Affiliation(s)
- Beatriz Escudero-Pérez
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Paula Ruibal
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Monika Rottstegge
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Anja Lüdtke
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Julia R Port
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Kristin Hartmann
- Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sergio Gómez-Medina
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Jürgen Müller-Guhl
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - Emily V Nelson
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
| | - Susanne Krasemann
- Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Estefanía Rodríguez
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - César Muñoz-Fontela
- Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg, Hamburg, Germany
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21
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Sarkar S, Heise MT. Mouse Models as Resources for Studying Infectious Diseases. Clin Ther 2019; 41:1912-1922. [PMID: 31540729 PMCID: PMC7112552 DOI: 10.1016/j.clinthera.2019.08.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/05/2019] [Accepted: 08/09/2019] [Indexed: 12/17/2022]
Abstract
Mouse models are important tools both for studying the pathogenesis of infectious diseases and for the preclinical evaluation of vaccines and therapies against a wide variety of human pathogens. The use of genetically defined inbred mouse strains, humanized mice, and gene knockout mice has allowed the research community to explore how pathogens cause disease, define the role of specific host genes in either controlling or promoting disease, and identify potential targets for the prevention or treatment of a wide range of infectious agents. This review discusses several of the most commonly used mouse model systems, as well as new resources such as the Collaborative Cross as models for studying infectious diseases.
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Affiliation(s)
- Sanjay Sarkar
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mark T Heise
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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22
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Escaffre O, Hill T, Ikegami T, Juelich TL, Smith JK, Zhang L, Perez DE, Atkins C, Park A, Lawrence WS, Sivasubramani SK, Peel JE, Peterson JW, Lee B, Freiberg AN. Experimental Infection of Syrian Hamsters With Aerosolized Nipah Virus. J Infect Dis 2019; 218:1602-1610. [PMID: 29912426 DOI: 10.1093/infdis/jiy357] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 06/12/2018] [Indexed: 01/08/2023] Open
Abstract
Background Nipah virus (NiV) is a paramyxovirus (genus Henipavirus) that can cause severe respiratory illness and encephalitis in humans. Transmission occurs through consumption of NiV-contaminated foods, and contact with NiV-infected animals or human body fluids. However, it is unclear whether aerosols derived from aforesaid sources or others also contribute to transmission, and current knowledge on NiV-induced pathogenicity after small-particle aerosol exposure is still limited. Methods Infectivity, pathogenicity, and real-time dissemination of aerosolized NiV in Syrian hamsters was evaluated using NiV-Malaysia (NiV-M) and/or its recombinant expressing firefly luciferase (rNiV-FlucNP). Results Both viruses had an equivalent pathogenicity in hamsters, which developed respiratory and neurological symptoms of disease, similar to using intranasal route, with no direct correlations to the dose. We showed that virus replication was predominantly initiated in the lower respiratory tract and, although delayed, also intensely in the oronasal cavity and possibly the brain, with gradual increase of signal in these regions until at least day 5-6 postinfection. Conclusion Hamsters infected with small-particle aerosolized NiV undergo similar clinical manifestations of the disease as previously described using liquid inoculum, and exhibit histopathological lesions consistent with NiV patient reports. NiV droplets could therefore play a role in transmission by close contact.
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Affiliation(s)
- Olivier Escaffre
- Department of Pathology, University of Texas Medical Branch, Galveston
| | - Terence Hill
- Department of Pathology, University of Texas Medical Branch, Galveston
| | - Tetsuro Ikegami
- Department of Pathology, University of Texas Medical Branch, Galveston.,Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston.,Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston
| | - Terry L Juelich
- Department of Pathology, University of Texas Medical Branch, Galveston
| | - Jennifer K Smith
- Department of Pathology, University of Texas Medical Branch, Galveston
| | - Lihong Zhang
- Department of Pathology, University of Texas Medical Branch, Galveston
| | - David E Perez
- Department of Pathology, University of Texas Medical Branch, Galveston
| | - Colm Atkins
- Department of Pathology, University of Texas Medical Branch, Galveston
| | - Arnold Park
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri
| | - William S Lawrence
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston
| | | | - Jennifer E Peel
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston
| | - Johnny W Peterson
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston.,Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston
| | - Benhur Lee
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Alexander N Freiberg
- Department of Pathology, University of Texas Medical Branch, Galveston.,Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston.,Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston
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23
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Mathieu C, Porotto M, Figueira TN, Horvat B, Moscona A. Fusion Inhibitory Lipopeptides Engineered for Prophylaxis of Nipah Virus in Primates. J Infect Dis 2019; 218:218-227. [PMID: 29566184 PMCID: PMC6009590 DOI: 10.1093/infdis/jiy152] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 03/15/2018] [Indexed: 11/14/2022] Open
Abstract
Background The emerging zoonotic paramyxovirus Nipah virus (NiV) causes severe respiratory and neurological disease in humans, with high fatality rates. Nipah virus can be transmitted via person-to-person contact, posing a high risk for epidemic outbreaks. However, a broadly applicable approach for human NiV outbreaks in field settings is lacking. Methods We engineered new antiviral lipopeptides and analyzed in vitro fusion inhibition to identify an optimal candidate for prophylaxis of NiV infection in the lower respiratory tract, and we assessed antiviral efficiency in 2 different animal models. Results We show that lethal NiV infection can be prevented with lipopeptides delivered via the respiratory route in both hamsters and nonhuman primates. By targeting retention of peptides for NiV prophylaxis in the respiratory tract, we avoid its systemic delivery in individuals who need only prevention, and thus we increase the safety of treatment and enhance utility of the intervention. Conclusions The experiments provide a proof of concept for the use of antifusion lipopeptides for prophylaxis of lethal NiV. These results advance the goal of rational development of potent lipopeptide inhibitors with desirable pharmacokinetic and biodistribution properties and a safe effective delivery method to target NiV and other pathogenic viruses.
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Affiliation(s)
- Cyrille Mathieu
- Department of Pediatrics, Columbia University Medical Center, New York.,Center for Host-Pathogen Interaction, Columbia University Medical Center, New York.,CIRI, International Center for Infectiology Research, Immunobiology of Viral Infections Team, Inserm, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, France
| | - Matteo Porotto
- Department of Pediatrics, Columbia University Medical Center, New York.,Center for Host-Pathogen Interaction, Columbia University Medical Center, New York
| | - Tiago N Figueira
- Department of Pediatrics, Columbia University Medical Center, New York.,Center for Host-Pathogen Interaction, Columbia University Medical Center, New York.,Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Branka Horvat
- CIRI, International Center for Infectiology Research, Immunobiology of Viral Infections Team, Inserm, University Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, France
| | - Anne Moscona
- Department of Pediatrics, Columbia University Medical Center, New York.,Department of Microbiology and Immunology, Columbia University Medical Center, New York.,Department of Physiology and Biophysics, Columbia University Medical Center, New York.,Center for Host-Pathogen Interaction, Columbia University Medical Center, New York
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24
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Thakur N, Bailey D. Advances in diagnostics, vaccines and therapeutics for Nipah virus. Microbes Infect 2019; 21:278-286. [PMID: 30817995 DOI: 10.1016/j.micinf.2019.02.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/08/2019] [Accepted: 02/11/2019] [Indexed: 12/22/2022]
Abstract
Nipah virus is an emerging zoonotic paramyxovirus that causes severe and often fatal respiratory and neurological disease in humans. The virus was first discovered after an outbreak of encephalitis in pig farmers in Malaysia and Singapore with subsequent outbreaks in Bangladesh or India occurring almost annually. Due to the highly pathogenic nature of NiV, its pandemic potential, and the lack of licensed vaccines or therapeutics, there is a requirement for research and development into highly sensitive and specific diagnostic tools as well as antivirals and vaccines to help prevent and control future outbreak situations.
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Affiliation(s)
- Nazia Thakur
- The Pirbright Institute, Pirbright, Woking, GU24 0NF, UK
| | - Dalan Bailey
- The Pirbright Institute, Pirbright, Woking, GU24 0NF, UK.
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25
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Kerry RG, Malik S, Redda YT, Sahoo S, Patra JK, Majhi S. Nano-based approach to combat emerging viral (NIPAH virus) infection. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2019; 18:196-220. [PMID: 30904587 PMCID: PMC7106268 DOI: 10.1016/j.nano.2019.03.004] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 02/19/2019] [Accepted: 03/11/2019] [Indexed: 12/28/2022]
Abstract
Emergence of new virus and their heterogeneity are growing at an alarming rate. Sudden outburst of Nipah virus (NiV) has raised serious question about their instant management using conventional medication and diagnostic measures. A coherent strategy with versatility and comprehensive perspective to confront the rising distress could perhaps be effectuated by implementation of nanotechnology. But in concurrent to resourceful and precise execution of nano-based medication, there is an ultimate need of concrete understanding of the NIV pathogenesis. Moreover, to amplify the effectiveness of nano-based approach in a conquest against NiV, a list of developed nanosystem with antiviral activity is also a prerequisite. Therefore the present review provides a meticulous cognizance of cellular and molecular pathogenesis of NiV. Conventional as well several nano-based diagnosis experimentations against viruses have been discussed. Lastly, potential efficacy of different forms of nano-based systems as convenient means to shield mankind against NiV has also been introduced.
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Affiliation(s)
- Rout George Kerry
- Post Graduate Department of Biotechnology, Utkal University, Vani Vihar, Bhubaneswar, Odisha, India
| | - Santosh Malik
- Departmentof Life Science, National Institute of Technology, Rourkela, Odisha, India
| | | | - Sabuj Sahoo
- Post Graduate Department of Biotechnology, Utkal University, Vani Vihar, Bhubaneswar, Odisha, India
| | - Jayanta Kumar Patra
- Research Institute of Biotechnology & Medical Converged Science, Dongguk University-Seoul, Goyangsi, Republic of Korea.
| | - Sanatan Majhi
- Post Graduate Department of Biotechnology, Utkal University, Vani Vihar, Bhubaneswar, Odisha, India.
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26
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Leon AJ, Borisevich V, Boroumand N, Seymour R, Nusbaum R, Escaffre O, Xu L, Kelvin DJ, Rockx B. Host gene expression profiles in ferrets infected with genetically distinct henipavirus strains. PLoS Negl Trop Dis 2018; 12:e0006343. [PMID: 29538374 PMCID: PMC5868854 DOI: 10.1371/journal.pntd.0006343] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 03/26/2018] [Accepted: 02/24/2018] [Indexed: 02/05/2023] Open
Abstract
Henipavirus infection causes severe respiratory and neurological disease in humans that can be fatal. To characterize the pathogenic mechanisms of henipavirus infection in vivo, we performed experimental infections in ferrets followed by genome-wide gene expression analysis of lung and brain tissues. The Hendra, Nipah-Bangladesh, and Nipah-Malaysia strains caused severe respiratory and neurological disease with animals succumbing around 7 days post infection. Despite the presence of abundant viral shedding, animal-to-animal transmission did not occur. The host gene expression profiles of the lung tissue showed early activation of interferon responses and subsequent expression of inflammation-related genes that coincided with the clinical deterioration. Additionally, the lung tissue showed unchanged levels of lymphocyte markers and progressive downregulation of cell cycle genes and extracellular matrix components. Infection in the brain resulted in a limited breadth of the host responses, which is in accordance with the immunoprivileged status of this organ. Finally, we propose a model of the pathogenic mechanisms of henipavirus infection that integrates multiple components of the host responses.
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Affiliation(s)
- Alberto J. Leon
- Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Viktoriya Borisevich
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States of America
- Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, United States of America
- Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States of America
| | - Nahal Boroumand
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States of America
| | - Robert Seymour
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States of America
- Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States of America
| | - Rebecca Nusbaum
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States of America
| | - Olivier Escaffre
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States of America
| | - Luoling Xu
- Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - David J. Kelvin
- Department of Microbiology and Immunology, Dalhousie University, Halifax, Canada
- International Institute of Infection and Immunity, Shantou University Medical College, Shantou, PRC
- * E-mail: (DJK); (BR)
| | - Barry Rockx
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States of America
- Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, United States of America
- Institute of Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States of America
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
- * E-mail: (DJK); (BR)
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27
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Yong KSM, Her Z, Chen Q. Humanized Mice as Unique Tools for Human-Specific Studies. Arch Immunol Ther Exp (Warsz) 2018; 66:245-266. [PMID: 29411049 PMCID: PMC6061174 DOI: 10.1007/s00005-018-0506-x] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 01/04/2018] [Indexed: 12/15/2022]
Abstract
With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis and test an array of novel therapeutics. In this review, “humanized” mice are defined as immunodeficient mouse engrafted with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This review will focus on the background of humanized mice, diseases, and human-specific therapeutics tested on this platform as well as solutions to improve humanized mice for future clinical use.
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Affiliation(s)
- Kylie Su Mei Yong
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Drive, Singapore, 138673, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore
| | - Zhisheng Her
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Drive, Singapore, 138673, Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Proteos, 61 Biopolis Drive, Singapore, 138673, Singapore.
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117545, Singapore.
- Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
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28
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Escaffre O, Saito TB, Juelich TL, Ikegami T, Smith JK, Perez DD, Atkins C, Levine CB, Huante MB, Nusbaum RJ, Endsley JJ, Freiberg AN, Rockx B. Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection. J Virol 2017; 91:e00275-17. [PMID: 28539439 PMCID: PMC5651721 DOI: 10.1128/jvi.00275-17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 05/11/2017] [Indexed: 12/27/2022] Open
Abstract
Nipah virus (NiV) is a zoonotic emerging paramyxovirus that can cause fatal respiratory illness or encephalitis in humans. Despite many efforts, the molecular mechanisms of NiV-induced acute lung injury (ALI) remain unclear. We previously showed that NiV replicates to high titers in human lung grafts in NOD-SCID/γ mice, resulting in a robust inflammatory response. Interestingly, these mice can undergo human immune system reconstitution by the bone marrow, liver, and thymus (BLT) reconstitution method, in addition to lung tissue engraftment, giving altogether a realistic model to study human respiratory viral infections. Here, we characterized NiV Bangladesh strain (NiV-B) infection of human lung grafts from human immune system-reconstituted mice in order to identify the overall effect of immune cells on NiV pathogenesis of the lung. We show that NiV-B replicated to high titers in human lung grafts and caused similar cytopathic effects irrespective of the presence of human leukocytes in mice. However, the human immune system interfered with virus spread across lung grafts, responded to infection by leukocyte migration to small airways and alveoli of the lung grafts, and accelerated oxidative stress in lung grafts. In addition, the presence of human leukocytes increased the expression of cytokines and chemokines that regulate inflammatory influx to sites of infection and tissue damage. These results advance our understanding of how the immune system limits NiV dissemination and contributes to ALI and inform efforts to identify therapeutic targets.IMPORTANCE Nipah virus (NiV) is an emerging paramyxovirus that can cause a lethal respiratory and neurological disease in humans. Only limited data are available on NiV pathogenesis in the human lung, and the relative contribution of the innate immune response and NiV to acute lung injury (ALI) is still unknown. Using human lung grafts in a human immune system-reconstituted mouse model, we showed that the NiV Bangladesh strain induced cytopathic lesions in lung grafts similar to those described in patients irrespective of the donor origin or the presence of leukocytes. However, the human immune system interfered with virus spread, responded to infection by leukocyte infiltration in the small airways and alveolar area, induced oxidative stress, and triggered the production of cytokines and chemokines that regulate inflammatory influx by leukocytes in response to infection. Understanding how leukocytes interact with NiV and cause ALI in human lung xenografts is crucial for identifying therapeutic targets.
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Affiliation(s)
- Olivier Escaffre
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Tais B Saito
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Terry L Juelich
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Tetsuro Ikegami
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Jennifer K Smith
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - David D Perez
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Colm Atkins
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Corri B Levine
- Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA
| | - Matthew B Huante
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Rebecca J Nusbaum
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Janice J Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Alexander N Freiberg
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA
- Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA
| | - Barry Rockx
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Viroscience, Erasmus University Medical Center, Rotterdam, The Netherlands
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Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD. Humanized Mouse Models of Clinical Disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2016; 12:187-215. [PMID: 27959627 DOI: 10.1146/annurev-pathol-052016-100332] [Citation(s) in RCA: 401] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immunodeficient mice engrafted with functional human cells and tissues, that is, humanized mice, have become increasingly important as small, preclinical animal models for the study of human diseases. Since the description of immunodeficient mice bearing mutations in the IL2 receptor common gamma chain (IL2rgnull) in the early 2000s, investigators have been able to engraft murine recipients with human hematopoietic stem cells that develop into functional human immune systems. These mice can also be engrafted with human tissues such as islets, liver, skin, and most solid and hematologic cancers. Humanized mice are permitting significant progress in studies of human infectious disease, cancer, regenerative medicine, graft-versus-host disease, allergies, and immunity. Ultimately, use of humanized mice may lead to the implementation of truly personalized medicine in the clinic. This review discusses recent progress in the development and use of humanized mice and highlights their utility for the study of human diseases.
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Affiliation(s)
- Nicole C Walsh
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Laurie L Kenney
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Sonal Jangalwe
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Ken-Edwin Aryee
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Dale L Greiner
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts 01605
| | - Michael A Brehm
- Department of Molecular Medicine, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts 01605
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Satterfield BA, Geisbert TW, Mire CE. Inhibition of the host antiviral response by Nipah virus: current understanding and future perspectives. Future Virol 2016. [DOI: 10.2217/fvl-2016-0027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Nipah virus (NiV) is a lethal paramyxovirus that has recently emerged as a human pathogen capable of causing acute respiratory disease and encephalitis. Like many viral pathogens, NiV has developed multiple means of antagonizing the host antiviral response. The viral proteins responsible for this antiviral inhibition are encoded in the NiV P gene and include the P, V, W and C proteins, which contain various unique and overlapping roles. This review examines the current data on inhibition of the host antiviral response for each of these proteins gathered from viral protein expression systems, in vitro data using recombinant NiV mutants and from in vivo studies using recombinant NiV mutants, as well as a future perspective regarding the direction of the field.
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Affiliation(s)
- Benjamin A Satterfield
- Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Thomas W Geisbert
- Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Chad E Mire
- Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
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31
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Escaffre O, Borisevich V, Vergara LA, Wen JW, Long D, Rockx B. Characterization of Nipah virus infection in a model of human airway epithelial cells cultured at an air-liquid interface. J Gen Virol 2016; 97:1077-1086. [PMID: 26932515 DOI: 10.1099/jgv.0.000441] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Nipah virus (NiV) is an emerging paramyxovirus that can cause lethal respiratory illness in humans. No vaccine/therapeutic is currently licensed for humans. Human-to-human transmission was previously reported during outbreaks and NiV could be isolated from respiratory secretions, but the proportion of cases in Malaysia exhibiting respiratory symptoms was significantly lower than that in Bangladesh. Previously, we showed that primary human basal respiratory epithelial cells are susceptible to both NiV-Malaysia (M) and -Bangladesh (B) strains causing robust pro-inflammatory responses. However, the cells of the human respiratory epithelium that NiV targets are unknown and their role in NiV transmission and NiV-related lung pathogenesis is still poorly understood. Here, we characterized NiV infection of the human respiratory epithelium using a model of the human tracheal/bronchial (B-ALI) and small airway (S-ALI) epithelium cultured at an air-liquid interface. We show that NiV-M and NiV-B infect ciliated and secretory cells in B/S-ALI, and that infection of S-ALI, but not B-ALI, results in disruption of the epithelium integrity and host responses recruiting human immune cells. Interestingly, NiV-B replicated more efficiently in B-ALI than did NiV-M. These results suggest that the human tracheal/bronchial epithelium is favourable to NiV replication and shedding, while inducing a limited host response. Our data suggest that the small airways epithelium is prone to inflammation and lesions as well as constituting a point of virus entry into the pulmonary vasculature. The use of relevant models of the human respiratory tract, such as B/S-ALI, is critical for understanding NiV-related lung pathogenesis and identifying the underlying mechanisms allowing human-to-human transmission.
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Affiliation(s)
- Olivier Escaffre
- Department of Pathology at University of Texas Medical Branch, Galveston, TX, USA
| | - Viktoriya Borisevich
- Department of Pathology at University of Texas Medical Branch, Galveston, TX, USA
| | - Leoncio A Vergara
- Center for Biomedical Engineering at University of Texas Medical Branch, Galveston, TX, USA
| | - Julie W Wen
- Department of Pathology at University of Texas Medical Branch, Galveston, TX, USA
| | - Dan Long
- Rocky Mountain Veterinary Branch, Microscopy Unit, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA
| | - Barry Rockx
- Department of Rare and Emerging Viral Infections and Response (EID), Centre for Infectious Disease Control (CIb), National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands.,Department of Pathology at University of Texas Medical Branch, Galveston, TX, USA
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Escaffre O, Halliday H, Borisevich V, Casola A, Rockx B. Oxidative stress in Nipah virus-infected human small airway epithelial cells. J Gen Virol 2015; 96:2961-2970. [PMID: 26297489 DOI: 10.1099/jgv.0.000243] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Nipah virus (NiV) is a zoonotic emerging pathogen that can cause severe and often fatal respiratory disease in humans. The pathogenesis of NiV infection of the human respiratory tract remains unknown. Reactive oxygen species (ROS) produced by airway epithelial cells in response to viral infections contribute to lung injury by inducing inflammation and oxidative stress; however, the role of ROS in NiV-induced respiratory disease is unknown. To investigate whether NiV induces oxidative stress in human respiratory epithelial cells, we used oxidative stress markers and monitored antioxidant gene expression. We also used ROS scavengers to assess their role in immune response modulation. Oxidative stress was confirmed in infected cells and correlated with the reduction in antioxidant enzyme gene expression. Infected cells treated by ROS scavengers resulted in a significant decrease of the (F2)-8-isoprostane marker, inflammatory responses and virus replication. In conclusion, ROS are induced during NiV infection in human respiratory epithelium and contribute to the inflammatory response. Understanding how oxidative stress contributes to NiV pathogenesis is crucial for therapeutic development.
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Affiliation(s)
- Olivier Escaffre
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | - Hailey Halliday
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA
| | | | - Antonella Casola
- Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.,Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Barry Rockx
- Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, USA.,Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.,Department of Rare and Emerging Viral Infections and Response, Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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The immunomodulating V and W proteins of Nipah virus determine disease course. Nat Commun 2015; 6:7483. [PMID: 26105519 PMCID: PMC4482017 DOI: 10.1038/ncomms8483] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 05/13/2015] [Indexed: 01/20/2023] Open
Abstract
The viral determinants that contribute to Nipah virus (NiV)-mediated disease are poorly understood compared with other paramyxoviruses. Here we use recombinant NiVs (rNiVs) to examine the contributions of the NiV V and W proteins to NiV pathogenesis in a ferret model. We show that a V-deficient rNiV is susceptible to the innate immune response in vitro and behaves as a replicating non-lethal virus in vivo. Remarkably, rNiV lacking W expression results in a delayed and altered disease course with decreased respiratory disease and increased terminal neurological disease associated with altered in vitro inflammatory cytokine production. This study confirms the V protein as the major determinant of pathogenesis, also being the first in vivo study to show that the W protein modulates the inflammatory host immune response in a manner that determines the disease course. Nipah virus (NiV) can be transmitted from bats and other animals to humans, causing severe encephalitis and respiratory disease. Here, Satterfield et al. show that the W protein of NiV modulates the host immune response and determines disease course in a ferret model of infection.
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Abstract
Many of the viral pathogens that cause infectious diseases in humans have a highly restricted species tropism, making the study of their pathogenesis and the development of clinical therapies difficult. The improvement of humanized mouse models over the past 30 years has greatly facilitated researchers' abilities to study host responses to viral infections in a cost effective and ethical manner. From HIV to hepatotropic viruses to Middle East Respiratory Syndrome coronavirus, humanized mice have led to the identification of factors crucial to the viral life cycle, served as an outlet for testing candidate therapies, and improved our abilities to analyze human immune responses to infection. In tackling both new and old viruses as they emerge, humanized mice will continue to be an indispensable tool.
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Affiliation(s)
- Jenna M Gaska
- Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544-1014, USA
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, 110 Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544-1014, USA.
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de Wit E, Munster VJ. Animal models of disease shed light on Nipah virus pathogenesis and transmission. J Pathol 2015; 235:196-205. [PMID: 25229234 DOI: 10.1002/path.4444] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 09/09/2014] [Accepted: 09/14/2014] [Indexed: 12/27/2022]
Abstract
Nipah virus is an emerging virus infection that causes yearly disease outbreaks with high case fatality rates in Bangladesh. Nipah virus causes encephalitis and systemic vasculitis, sometimes in combination with respiratory disease. Pteropus species fruit bats are the natural reservoir of Nipah virus and zoonotic transmission can occur directly or via an intermediate host; human-to-human transmission occurs regularly. In this review we discuss the current state of knowledge on the pathogenesis and transmission of Nipah virus, focusing on dissemination of the virus through its host, known determinants of pathogenicity and routes of zoonotic and human-to-human transmission. Since data from human cases are sparse, this knowledge is largely based on the results of studies performed in animal models that recapitulate Nipah virus disease in humans.
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Affiliation(s)
- Emmie de Wit
- Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA
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Spade DJ, McDonnell EV, Heger NE, Sanders JA, Saffarini CM, Gruppuso PA, De Paepe ME, Boekelheide K. Xenotransplantation models to study the effects of toxicants on human fetal tissues. ACTA ACUST UNITED AC 2014; 101:410-22. [PMID: 25477288 DOI: 10.1002/bdrb.21131] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/14/2014] [Indexed: 12/11/2022]
Abstract
Many diseases that manifest throughout the lifetime are influenced by factors affecting fetal development. Fetal exposure to xenobiotics, in particular, may influence the development of adult diseases. Established animal models provide systems for characterizing both developmental biology and developmental toxicology. However, animal model systems do not allow researchers to assess the mechanistic effects of toxicants on developing human tissue. Human fetal tissue xenotransplantation models have recently been implemented to provide human-relevant mechanistic data on the many tissue-level functions that may be affected by fetal exposure to toxicants. This review describes the development of human fetal tissue xenotransplant models for testis, prostate, lung, liver, and adipose tissue, aimed at studying the effects of xenobiotics on tissue development, including implications for testicular dysgenesis, prostate disease, lung disease, and metabolic syndrome. The mechanistic data obtained from these models can complement data from epidemiology, traditional animal models, and in vitro studies to quantify the risks of toxicant exposures during human development.
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Affiliation(s)
- Daniel J Spade
- Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island
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