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Bahojb Mahdavi SZ, Jebelli A, Aghbash PS, Baradaran B, Amini M, Oroojalian F, Pouladi N, Baghi HB, de la Guardia M, Mokhtarzadeh AA. A comprehensive overview on the crosstalk between microRNAs and viral pathogenesis and infection. Med Res Rev 2025; 45:349-425. [PMID: 39185567 PMCID: PMC11796338 DOI: 10.1002/med.22073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 04/11/2023] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
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Affiliation(s)
- Seyedeh Zahra Bahojb Mahdavi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Asiyeh Jebelli
- Department of Biological Science, Faculty of Basic ScienceHigher Education Institute of Rab‐RashidTabrizIran
- Tuberculosis and Lung Diseases Research CenterTabriz University of Medical SciencesTabrizIran
| | | | - Behzad Baradaran
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Mohammad Amini
- Immunology Research CenterTabriz University of Medical SciencesTabrizIran
| | - Fatemeh Oroojalian
- Department of Advanced Sciences and Technologies in Medicine, School of MedicineNorth Khorasan University of Medical SciencesBojnurdIran
| | - Nasser Pouladi
- Department of Biology, Faculty of Basic SciencesAzarbaijan Shahid Madani UniversityTabrizIran
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2
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Tugizov S. HIV-1 Tat-induced disruption of epithelial junctions and epithelial-mesenchymal transition of oral and genital epithelial cells lead to increased invasiveness of neoplastic cells and the spread of herpes simplex virus and cytomegalovirus. Front Immunol 2025; 16:1541532. [PMID: 40018040 PMCID: PMC11866325 DOI: 10.3389/fimmu.2025.1541532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/28/2025] [Indexed: 03/01/2025] Open
Abstract
Human immunodeficiency virus (HIV-1) transactivator Tat is a unique multi-functional viral protein secreted by infected cells. Although its primary function is to promote HIV-1 transcription, secreted Tat interacts with neighboring cells and induces numerous disease-associated pathological changes. Despite the substantial reduction of viral load and disease burden, Tat expression and secretion persist in people living with HIV who are undergoing treatment with highly effective combination antiretroviral therapy (cART). Tat interacts with both oral and genital epithelial cells and impairs their mucosal barrier functions, which facilitates the entry of other pathogenic viruses. Tat-mediated interactions with both human papillomavirus (HPV) -infected and HPV-negative neoplastic epithelial cells lead to epithelial-mesenchymal transition and increased invasiveness of malignant cells. Likewise, Tat-induced disruption of oral epithelial cell junctions leads to herpes simplex virus-1 (HSV-1) infection and spread via exposure of its receptor, nectin-1. HIV-1 Tat facilitates infection and spread of human cytomegalovirus (HCMV) by activating mitogen-activated protein kinases (MAPK) and promoting NF-κB signaling, both critical for the replication and production of progeny virions. HIV extracellular Tat also plays a critical role in human herpesvirus 8 (HHV8) -caused Kaposi sarcoma (KS) pathogenesis by synergizing with HHV-8 lytic proteins and promoting the proliferation, angiogenesis, and migration of endothelial cells. Collectively, these findings emphasize the critical impact of HIV-1 Tat on HIV/AIDS pathogenesis during the cART era and highlight the need for further research on the molecular mechanisms underlying Tat-mediated interactions with oral and genital mucosal epithelial cells.
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Affiliation(s)
- Sharof Tugizov
- Department of Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA, United States
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3
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Spalinger MR, Sanati G, Chatterjee P, Hai R, Li J, Santos AN, Nordgren TM, Tremblay ML, Eckmann L, Hanson E, Scharl M, Wu X, Boland BS, McCole DF. Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene. Cell Mol Gastroenterol Hepatol 2025:101447. [PMID: 39756517 DOI: 10.1016/j.jcmgh.2024.101447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 12/18/2024] [Accepted: 12/19/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND & AIMS Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus. RESULTS We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib. CONCLUSION Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry and identify a clinically approved therapeutic agent to mitigate this risk.
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Affiliation(s)
- Marianne R Spalinger
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California; Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland
| | - Golshid Sanati
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California
| | - Pritha Chatterjee
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California
| | - Rong Hai
- Department of Microbiology and Plant Pathology, University of California Riverside, Riverside, California
| | - Jiang Li
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California
| | - Alina N Santos
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California
| | - Tara M Nordgren
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California; Current position: College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado
| | - Michel L Tremblay
- Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
| | - Lars Eckmann
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Elaine Hanson
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, and University of Zurich, Zurich, Switzerland
| | - Xiwei Wu
- Integrative Genomics Core, Beckman Research Institute of City of Hope, Monrovia, California
| | - Brigid S Boland
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Declan F McCole
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, California.
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4
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Chuang YC, Ou JHJ. Hepatitis B virus entry, assembly, and egress. Microbiol Mol Biol Rev 2024; 88:e0001424. [PMID: 39440957 DOI: 10.1128/mmbr.00014-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024] Open
Abstract
SUMMARYHepatitis B virus (HBV) is an important human pathogen that chronically infects approximately 250 million people in the world, resulting in ~1 million deaths annually. This virus is a hepatotropic virus and can cause severe liver diseases including cirrhosis and hepatocellular carcinoma. The entry of HBV into hepatocytes is initiated by the interaction of its envelope proteins with its receptors. This is followed by the delivery of the viral nucleocapsid to the nucleus for the release of its genomic DNA and the transcription of viral RNAs. The assembly of the viral capsid particles may then take place in the nucleus or the cytoplasm and may involve cellular membranes. This is followed by the egress of the virus from infected cells. In recent years, significant research progresses had been made toward understanding the entry, the assembly, and the egress of HBV particles. In this review, we discuss the molecular pathways of these processes and compare them with those used by hepatitis delta virus and hepatitis C virus , two other hepatotropic viruses that are also enveloped. The understanding of these processes will help us to understand how HBV replicates and causes diseases, which will help to improve the treatments for HBV patients.
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Affiliation(s)
- Yu-Chen Chuang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
| | - J-H James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA
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5
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Nagarathinam K, Scheck A, Labuhn M, Ströh LJ, Herold E, Veselkova B, Tune S, Cramer JT, Rosset S, Vollers SS, Bankwitz D, Ballmaier M, Böning H, Roth E, Khera T, Ahsendorf-Abidi HP, Dittrich-Breiholz O, Obleser J, Nassal M, Jäck HM, Pietschmann T, Correia BE, Krey T. Epitope-focused immunogens targeting the hepatitis C virus glycoproteins induce broadly neutralizing antibodies. SCIENCE ADVANCES 2024; 10:eado2600. [PMID: 39642219 PMCID: PMC11623273 DOI: 10.1126/sciadv.ado2600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 11/04/2024] [Indexed: 12/08/2024]
Abstract
Hepatitis C virus (HCV) infection causes ~290,000 annual human deaths despite the highly effective antiviral treatment available. Several viral immune evasion mechanisms have hampered the development of an effective vaccine against HCV, among them the remarkable conformational flexibility within neutralization epitopes in the HCV antigens. Here, we report the design of epitope-focused immunogens displaying two distinct HCV cross-neutralization epitopes. We show that these immunogens induce a pronounced, broadly neutralizing antibody response in laboratory and transgenic human antibody mice. Monoclonal human antibodies isolated from immunized human antibody mice specifically recognized the grafted epitopes and neutralized four diverse HCV strains. Our results highlight a promising strategy for developing HCV immunogens and provide an encouraging paradigm for targeting structurally flexible epitopes to improve the induction of neutralizing antibodies.
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Affiliation(s)
- Kumar Nagarathinam
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
| | - Andreas Scheck
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Maurice Labuhn
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | - Luisa J. Ströh
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
| | - Elisabeth Herold
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
| | - Barbora Veselkova
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
| | - Sarah Tune
- Department of Psychology, University of Lübeck, 23562 Lübeck, Germany
- Center of Brain, Behavior, and Metabolism, University of Lübeck, 23562 Lübeck, Germany
| | | | - Stéphane Rosset
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Sabrina S. Vollers
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Dorothea Bankwitz
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | - Matthias Ballmaier
- Central Research Facility Cell Sorting, Hannover Medical School, 30625 Hannover, Germany
| | - Heike Böning
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
| | - Edith Roth
- Division of Molecular Immunology, Department of Internal Medicine 3, Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tanvi Khera
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
| | | | | | - Jonas Obleser
- Department of Psychology, University of Lübeck, 23562 Lübeck, Germany
- Center of Brain, Behavior, and Metabolism, University of Lübeck, 23562 Lübeck, Germany
| | - Michael Nassal
- Department of Internal Medicine 2/Molecular Biology, University Hospital Freiburg, 79106 Freiburg, Germany
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Department of Internal Medicine 3, Friedrich-Alexander University of Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Thomas Pietschmann
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, 30625 Hannover, Germany
- Excellence Cluster 2155 RESIST, Hannover Medical School, 30625 Hannover, Germany
| | - Bruno E. Correia
- Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne CH-1015, Switzerland
| | - Thomas Krey
- Institute of Biochemistry, Center of Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
- Excellence Cluster 2155 RESIST, Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, 38124 Braunschweig, Germany
- Centre for Structural Systems Biology (CSSB), 22607 Hamburg, Germany
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See WR, Yousefi M, Ooi YS. A review of virus host factor discovery using CRISPR screening. mBio 2024; 15:e0320523. [PMID: 39422472 PMCID: PMC11559068 DOI: 10.1128/mbio.03205-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024] Open
Abstract
The emergence of genome-scale forward genetic screening techniques, such as Haploid Genetic screen and clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen has opened new horizons in our understanding of virus infection biology. CRISPR screening has become a popular tool for the discovery of novel host factors for several viruses due to its specificity and efficiency in genome editing. Here, we review how CRISPR screening has revolutionized our understanding of virus-host interactions from scientific and technological viewpoints. A summary of the published screens conducted thus far to uncover virus host factors is presented, highlighting their experimental design and significant findings. We will outline relevant methods for customizing the CRISPR screening process to answer more specific hypotheses and compile a glossary of conducted CRISPR screens to show their design aspects. Furthermore, using flaviviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as examples, we hope to offer a broad-based perspective on the capabilities of CRISPR screening to serve as a reference point to guide future unbiased discovery of virus host factors.
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Affiliation(s)
- Wayne Ren See
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
| | - Meisam Yousefi
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
| | - Yaw Shin Ooi
- Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore
- Infectious Diseases Labs (A*STAR ID Labs), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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7
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Ke PY, Yeh CT. Functional Role of Hepatitis C Virus NS5A in the Regulation of Autophagy. Pathogens 2024; 13:980. [PMID: 39599533 PMCID: PMC11597459 DOI: 10.3390/pathogens13110980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 10/30/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
Many types of RNA viruses, including the hepatitis C virus (HCV), activate autophagy in infected cells to promote viral growth and counteract the host defense response. Autophagy acts as a catabolic pathway in which unnecessary materials are removed via the lysosome, thus maintaining cellular homeostasis. The HCV non-structural 5A (NS5A) protein is a phosphoprotein required for viral RNA replication, virion assembly, and the determination of interferon (IFN) sensitivity. Recently, increasing evidence has shown that HCV NS5A can induce autophagy to promote mitochondrial turnover and the degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) and diacylglycerol acyltransferase 1 (DGAT1). In this review, we summarize recent progress in understanding the detailed mechanism by which HCV NS5A triggers autophagy, and outline the physiological significance of the balance between host-virus interactions.
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Affiliation(s)
- Po-Yuan Ke
- Department of Biochemistry and Molecular Biology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan;
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8
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Chen J, Fang M, Li Y, Ding H, Zhang X, Jiang X, Zhang J, Zhang C, Lu Z, Luo M. Cell surface protein-protein interaction profiling for biological network analysis and novel target discovery. LIFE MEDICINE 2024; 3:lnae031. [PMID: 39872863 PMCID: PMC11749001 DOI: 10.1093/lifemedi/lnae031] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 08/28/2024] [Indexed: 01/30/2025]
Abstract
The secretome is composed of cell surface membrane proteins and extracellular secreted proteins that are synthesized via secretory machinery, accounting for approximately one-third of human protein-encoding genes and playing central roles in cellular communication with the external environment. Secretome protein-protein interactions (SPPIs) mediate cell proliferation, apoptosis, and differentiation, as well as stimulus- or cell-specific responses that regulate a diverse range of biological processes. Aberrant SPPIs are associated with diseases including cancer, immune disorders, and illness caused by infectious pathogens. Identifying the receptor/ligand for a secretome protein or pathogen can be a challenging task, and many SPPIs remain obscure, with a large number of orphan receptors and ligands, as well as viruses with unknown host receptors, populating the SPPI network. In addition, proteins with known receptors/ligands may also interact with alternative uncharacterized partners and exert context-dependent effects. In the past few decades, multiple varied approaches have been developed to identify SPPIs, and these methods have broad applications in both basic and translational research. Here, we review and discuss the technologies for SPPI profiling and the application of these technologies in identifying novel targets for immunotherapy and anti-infectious agents.
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Affiliation(s)
- Jiaojiao Chen
- Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Maoxin Fang
- Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yuwei Li
- Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Haodong Ding
- Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Xinyu Zhang
- Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Xiaoyi Jiang
- Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Jinlan Zhang
- The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai 200240, China
| | - Chengcheng Zhang
- Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhigang Lu
- The Fifth People’s Hospital of Shanghai, Fudan University, Shanghai 200240, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Min Luo
- Institute of Pediatrics, Children’s Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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9
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Brychka D, Ayala-Nunez NV, Dupas A, Bare Y, Partiot E, Mittelheisser V, Lucansky V, Goetz JG, Osmani N, Gaudin R. Targeting monocytic Occludin impairs transendothelial migration and HIV neuroinvasion. EMBO Rep 2024; 25:3276-3299. [PMID: 39039298 PMCID: PMC11315906 DOI: 10.1038/s44319-024-00190-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 06/11/2024] [Accepted: 06/17/2024] [Indexed: 07/24/2024] Open
Abstract
Transmigration of circulating monocytes from the bloodstream to tissues represents an early hallmark of inflammation. This process plays a pivotal role during viral neuroinvasion, encephalitis, and HIV-associated neurocognitive disorders. How monocytes locally unzip endothelial tight junction-associated proteins (TJAPs), without perturbing impermeability, to reach the central nervous system remains poorly understood. Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through endothelial cells. We found that human monocytic OCLN (hmOCLN) clusters at monocyte-endothelium interface, while modulation of hmOCLN expression significantly impacts monocyte transmigration. Furthermore, we designed OCLN-derived peptides targeting its extracellular loops (EL) and show that transmigration of treated monocytes is inhibited in vitro and in zebrafish embryos, while preserving vascular integrity. Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and we found that the OCLN-derived peptides significantly inhibit HIV dissemination to cerebral organoids. In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent monocyte infiltration and viral neuroinvasion.
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Affiliation(s)
- Diana Brychka
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
| | - Nilda Vanesa Ayala-Nunez
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
- Empa - Swiss Federal Laboratories for Materials Science and Technology, Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland
| | - Amandine Dupas
- Tumor Biomechanics, INSERM UMR_S1109, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Equipe Labellisée Ligue Contre le Cancer, Strasbourg, France
| | - Yonis Bare
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
| | - Emma Partiot
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
| | - Vincent Mittelheisser
- Tumor Biomechanics, INSERM UMR_S1109, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Equipe Labellisée Ligue Contre le Cancer, Strasbourg, France
| | - Vincent Lucansky
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France
- Univ Montpellier, Montpellier, France
- Jessenius Faculty of Medicine in Martin (JFMED CU), Department of Pathophysiology, Comenius University in Bratislava, Martin, Slovakia
| | - Jacky G Goetz
- Tumor Biomechanics, INSERM UMR_S1109, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Equipe Labellisée Ligue Contre le Cancer, Strasbourg, France
| | - Naël Osmani
- Tumor Biomechanics, INSERM UMR_S1109, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
- Equipe Labellisée Ligue Contre le Cancer, Strasbourg, France
| | - Raphael Gaudin
- CNRS, Institut de Recherche en Infectiologie de Montpellier (IRIM), Montpellier, France.
- Univ Montpellier, Montpellier, France.
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10
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De Meyer A, Meuleman P. Preclinical animal models to evaluate therapeutic antiviral antibodies. Antiviral Res 2024; 225:105843. [PMID: 38548022 DOI: 10.1016/j.antiviral.2024.105843] [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: 01/29/2024] [Accepted: 02/25/2024] [Indexed: 04/05/2024]
Abstract
Despite the availability of effective preventative vaccines and potent small-molecule antiviral drugs, effective non-toxic prophylactic and therapeutic measures are still lacking for many viruses. The use of monoclonal and polyclonal antibodies in an antiviral context could fill this gap and provide effective virus-specific medical interventions. In order to develop these therapeutic antibodies, preclinical animal models are of utmost importance. Due to the variability in viral pathogenesis, immunity and overall characteristics, the most representative animal model for human viral infection differs between virus species. Therefore, throughout the years researchers sought to find the ideal preclinical animal model for each virus. The most used animal models in preclinical research include rodents (mice, ferrets, …) and non-human primates (macaques, chimpanzee, ….). Currently, antibodies are tested for antiviral efficacy against a variety of viruses including different hepatitis viruses, human immunodeficiency virus (HIV), influenza viruses, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rabies virus. This review provides an overview of the current knowledge about the preclinical animal models that are used for the evaluation of therapeutic antibodies for the abovementioned viruses.
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Affiliation(s)
- Amse De Meyer
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
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11
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Tang X, Xu S, Yang Z, Wang K, Dai K, Zhang Y, Hu B, Wang Y, Cao S, Huang X, Yan Q, Wu R, Zhao Q, Du S, Wen X, Wen Y. EspP2 Regulates the Adhesion of Glaesserella parasuis via Rap1 Signaling Pathway. Int J Mol Sci 2024; 25:4570. [PMID: 38674155 PMCID: PMC11050538 DOI: 10.3390/ijms25084570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/07/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
Abstract
Different levels of EspP2 expression are seen in strains of Glaesserella parasuis with high and low pathogenicity. As a potential virulence factor for G. parasuis, the pathogenic mechanism of EspP2 in infection of host cells is not clear. To begin to elucidate the effect of EspP2 on virulence, we used G. parasuis SC1401 in its wild-type form and SC1401, which was made EspP2-deficient. We demonstrated that EspP2 causes up-regulation of claudin-1 and occludin expression, thereby promoting the adhesion of G. parasuis to host cells; EspP2-deficiency resulted in significantly reduced adhesion of G. parasuis to cells. Transcriptome sequencing analysis of EspP2-treated PK15 cells revealed that the Rap1 signaling pathway is stimulated by EspP2. Blocking this pathway diminished occludin expression and adhesion. These results indicated that EspP2 regulates the adhesion of Glaesserella parasuis via Rap1 signaling pathway.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Yiping Wen
- Research Center of Swine Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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12
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Woo J, Choi Y. Biomarkers in Detection of Hepatitis C Virus Infection. Pathogens 2024; 13:331. [PMID: 38668286 PMCID: PMC11054098 DOI: 10.3390/pathogens13040331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/29/2024] Open
Abstract
The hepatitis C virus (HCV) infection affects 58 million people worldwide. In the United States, the incidence rate of acute hepatitis C has doubled since 2014; during 2021, this increased to 5% from 2020. Acute hepatitis C is defined by any symptom of acute viral hepatitis plus either jaundice or elevated serum alanine aminotransferase (ALT) activity with the detection of HCV RNA, the anti-HCV antibody, or hepatitis C virus antigen(s). However, most patients with acute infection are asymptomatic. In addition, ALT activity and HCV RNA levels can fluctuate, and a delayed detection of the anti-HCV antibody can occur among some immunocompromised persons with HCV infection. The detection of specific biomarkers can be of great value in the early detection of HCV infection at an asymptomatic stage. The high rate of HCV replication (which is approximately 1010 to 1012 virions per day) and the lack of proofreading by the viral RNA polymerase leads to enormous genetic diversity, creating a major challenge for the host immune response. This broad genetic diversity contributes to the likelihood of developing chronic infection, thus leading to the development of cirrhosis and liver cancer. Direct-acting antiviral (DAA) therapies for HCV infection are highly effective with a cure rate of up to 99%. At the same time, many patients with HCV infection are unaware of their infection status because of the mostly asymptomatic nature of hepatitis C, so they remain undiagnosed until the liver damage has advanced. Molecular mechanisms induced by HCV have been intensely investigated to find biomarkers for diagnosing the acute and chronic phases of the infection. However, there are no clinically verified biomarkers for patients with hepatitis C. In this review, we discuss the biomarkers that can differentiate acute from chronic hepatitis C, and we summarize the current state of the literature on the useful biomarkers that are detectable during acute and chronic HCV infection, liver fibrosis/cirrhosis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
| | - Youkyung Choi
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, US Centers for Disease Control and Prevention (CDC), Atlanta, GA 30329-4018, USA;
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13
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Herron ICT, Laws TR, Nelson M. Marmosets as models of infectious diseases. Front Cell Infect Microbiol 2024; 14:1340017. [PMID: 38465237 PMCID: PMC10921895 DOI: 10.3389/fcimb.2024.1340017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/29/2024] [Indexed: 03/12/2024] Open
Abstract
Animal models of infectious disease often serve a crucial purpose in obtaining licensure of therapeutics and medical countermeasures, particularly in situations where human trials are not feasible, i.e., for those diseases that occur infrequently in the human population. The common marmoset (Callithrix jacchus), a Neotropical new-world (platyrrhines) non-human primate, has gained increasing attention as an animal model for a number of diseases given its small size, availability and evolutionary proximity to humans. This review aims to (i) discuss the pros and cons of the common marmoset as an animal model by providing a brief snapshot of how marmosets are currently utilized in biomedical research, (ii) summarize and evaluate relevant aspects of the marmoset immune system to the study of infectious diseases, (iii) provide a historical backdrop, outlining the significance of infectious diseases and the importance of developing reliable animal models to test novel therapeutics, and (iv) provide a summary of infectious diseases for which a marmoset model exists, followed by an in-depth discussion of the marmoset models of two studied bacterial infectious diseases (tularemia and melioidosis) and one viral infectious disease (viral hepatitis C).
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Affiliation(s)
- Ian C. T. Herron
- CBR Division, Defence Science and Technology Laboratory (Dstl), Salisbury, United Kingdom
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14
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Li Y, Xiong Z, Jiang WL, Tian D, Zhou H, Hou Q, Xiao L, Zhang M, Huang L, Zhong L, Zhou L, Zeng GG. An innovative viewpoint on the existing and prospectiveness of SR-B1. Curr Probl Cardiol 2024; 49:102226. [PMID: 38040207 DOI: 10.1016/j.cpcardiol.2023.102226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 11/28/2023] [Indexed: 12/03/2023]
Abstract
Scavenger Receptor Class B Type 1 (SR-B1), a receptor protein expressed on the cell membrane, plays a crucial role in the metabolism and transport of cholesterol and other lipids, contributing significantly to the homeostasis of lipid levels within the body. Bibliometric analysis involves the application of mathematical and statistical methods to quantitatively analyze different types of documents. It involves the analysis of structural and temporal trends in scholarly articles, coupled with the identification of subject emphasis and variations. Through a bibliometric analysis, this study examines the historical background, current research trends, and future directions in the exploration of SR-B1. By offering insights into the research status and development of SR-B1, this paper aims to assist researchers in identifying novel pathways and areas of investigation in this field of study. Following the screening process, it can be concluded that research on SR-B1 has consistently remained a topic of significant interest over the past 17 years. Interestingly, SR-B1 has recently garnered attention in areas beyond its traditional research focus, including the field of cancer. The primary objective of this review is to provide a concise and accessible overview of the development process of SR-B1 that can help readers who are not well-versed in SR-B1 research quickly grasp its key aspects. Furthermore, this review aims to offer insights and suggestions to researchers regarding potential future research directions and areas of emphasis relating to SR-B1.
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Affiliation(s)
- Yonggui Li
- The Second Affiliated Hospital, Department of Digestive Internal Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhijie Xiong
- The Second Affiliated Hospital, Department of Digestive Internal Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Wan-Li Jiang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Departments of Clinical Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Dandan Tian
- School of Nursing, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Haiyou Zhou
- The Second Affiliated Hospital, Department of Digestive Internal Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; 2020 Grade Excellent Doctor Class of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Qin Hou
- Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Liang Xiao
- The Second Affiliated Hospital, Department of Digestive Internal Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; 2020 Grade Excellent Doctor Class of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Mengjie Zhang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Departments of Clinical Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Liubin Huang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Departments of Clinical Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Lianping Zhong
- The Second Affiliated Hospital, Department of Digestive Internal Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Department of Gastroenterology, the Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Li Zhou
- Department of Pathology, Chongqing Public Health Medical Center, Southwest University Public Health Hospital, Chongqing, China
| | - Guang-Gui Zeng
- The Second Affiliated Hospital, Department of Digestive Internal Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; 2020 Grade Excellent Doctor Class of Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
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15
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Xu ZS, Du WT, Wang SY, Wang MY, Yang YN, Li YH, Li ZQ, Zhao LX, Yang Y, Luo WW, Wang YY. LDLR is an entry receptor for Crimean-Congo hemorrhagic fever virus. Cell Res 2024; 34:140-150. [PMID: 38182887 PMCID: PMC10837205 DOI: 10.1038/s41422-023-00917-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 12/14/2023] [Indexed: 01/07/2024] Open
Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-born zoonotic bunyavirus that causes severe hemorrhagic fever and death in humans. CCHFV enters the cell via clathrin-mediated endocytosis which is dependent on its surface glycoproteins. However, the cellular receptors that are required for CCHFV entry are unknown. Here we show that the low density lipoprotein receptor (LDLR) is an entry receptor for CCHFV. Genetic knockout of LDLR impairs viral infection in various CCHFV-susceptible human, monkey and mouse cells, which is restored upon reconstitution with ectopically-expressed LDLR. Mutagenesis studies indicate that the ligand binding domain (LBD) of LDLR is necessary for CCHFV infection. LDLR binds directly to CCHFV glycoprotein Gc with high affinity, which supports virus attachment and internalization into host cells. Consistently, a soluble sLDLR-Fc fusion protein or anti-LDLR blocking antibodies impair CCHFV infection into various susceptible cells. Furthermore, genetic knockout of LDLR or administration of an LDLR blocking antibody significantly reduces viral loads, pathological effects and death following CCHFV infection in mice. Our findings suggest that LDLR is an entry receptor for CCHFV and pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever.
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Affiliation(s)
- Zhi-Sheng Xu
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Wen-Tian Du
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Su-Yun Wang
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Mo-Yu Wang
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yi-Ning Yang
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yu-Hui Li
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhen-Qi Li
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Li-Xin Zhao
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yan Yang
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Wei-Wei Luo
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yan-Yi Wang
- Wuhan Institute of Virology, Center for Biosafety Mega-science, Chinese Academy of Sciences, Wuhan, Hubei, China.
- Key Laboratory of Virology and Biosafety, Chinese Academy of Sciences, Wuhan, Hubei, China.
- University of Chinese Academy of Sciences, Beijing, China.
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16
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Badawi AH, Mohamad NA, Stanslas J, Kirby BP, Neela VK, Ramasamy R, Basri H. In Vitro Blood-Brain Barrier Models for Neuroinfectious Diseases: A Narrative Review. Curr Neuropharmacol 2024; 22:1344-1373. [PMID: 38073104 PMCID: PMC11092920 DOI: 10.2174/1570159x22666231207114346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/04/2022] [Accepted: 11/25/2022] [Indexed: 05/16/2024] Open
Abstract
The blood-brain barrier (BBB) is a complex, dynamic, and adaptable barrier between the peripheral blood system and the central nervous system. While this barrier protects the brain and spinal cord from inflammation and infection, it prevents most drugs from reaching the brain tissue. With the expanding interest in the pathophysiology of BBB, the development of in vitro BBB models has dramatically evolved. However, due to the lack of a standard model, a range of experimental protocols, BBB-phenotype markers, and permeability flux markers was utilized to construct in vitro BBB models. Several neuroinfectious diseases are associated with BBB dysfunction. To conduct neuroinfectious disease research effectively, there stems a need to design representative in vitro human BBB models that mimic the BBB's functional and molecular properties. The highest necessity is for an in vitro standardised BBB model that accurately represents all the complexities of an intact brain barrier. Thus, this in-depth review aims to describe the optimization and validation parameters for building BBB models and to discuss previous research on neuroinfectious diseases that have utilized in vitro BBB models. The findings in this review may serve as a basis for more efficient optimisation, validation, and maintenance of a structurally- and functionally intact BBB model, particularly for future studies on neuroinfectious diseases.
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Affiliation(s)
- Ahmad Hussein Badawi
- Department of Neurology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Nur Afiqah Mohamad
- Department of Neurology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
- Centre for Foundation Studies, Lincoln University College, 47301, Petaling Jaya, Selangor, Malaysia
| | - Johnson Stanslas
- Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Brian Patrick Kirby
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Vasantha Kumari Neela
- Department of Medical Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Rajesh Ramasamy
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Hamidon Basri
- Department of Neurology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
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17
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Bartosh UI, Dome AS, Zhukova NV, Karitskaya PE, Stepanov GA. CRISPR/Cas9 as a New Antiviral Strategy for Treating Hepatitis Viral Infections. Int J Mol Sci 2023; 25:334. [PMID: 38203503 PMCID: PMC10779197 DOI: 10.3390/ijms25010334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/19/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatitis is an inflammatory liver disease primarily caused by hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV) viruses. The chronic forms of hepatitis resulting from HBV and HCV infections can progress to cirrhosis or hepatocellular carcinoma (HCC), while acute hepatitis can lead to acute liver failure, sometimes resulting in fatality. Viral hepatitis was responsible for over 1 million reported deaths annually. The treatment of hepatitis caused by viral infections currently involves the use of interferon-α (IFN-α), nucleoside inhibitors, and reverse transcriptase inhibitors (for HBV). However, these methods do not always lead to a complete cure for viral infections, and chronic forms of the disease pose significant treatment challenges. These facts underscore the urgent need to explore novel drug developments for the treatment of viral hepatitis. The discovery of the CRISPR/Cas9 system and the subsequent development of various modifications of this system have represented a groundbreaking advance in the quest for innovative strategies in the treatment of viral infections. This technology enables the targeted disruption of specific regions of the genome of infectious agents or the direct manipulation of cellular factors involved in viral replication by introducing a double-strand DNA break, which is targeted by guide RNA (spacer). This review provides a comprehensive summary of our current knowledge regarding the application of the CRISPR/Cas system in the regulation of viral infections caused by HAV, HBV, and HCV. It also highlights new strategies for drug development aimed at addressing both acute and chronic forms of viral hepatitis.
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Affiliation(s)
| | | | | | | | - Grigory A. Stepanov
- The Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, Novosibirsk 630090, Russia; (U.I.B.); (A.S.D.); (N.V.Z.); (P.E.K.)
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18
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So CW, Sourisseau M, Sarwar S, Evans MJ, Randall G. Roles of epidermal growth factor receptor, claudin-1 and occludin in multi-step entry of hepatitis C virus into polarized hepatoma spheroids. PLoS Pathog 2023; 19:e1011887. [PMID: 38157366 PMCID: PMC10756512 DOI: 10.1371/journal.ppat.1011887] [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: 08/17/2023] [Accepted: 12/06/2023] [Indexed: 01/03/2024] Open
Abstract
The multi-step process of hepatitis C virus (HCV) entry is facilitated by various host factors, including epidermal growth factor receptor (EGFR) and the tight junction proteins claudin-1 (CLDN1) and occludin (OCLN), which are thought to function at later stages of the HCV entry process. Using single particle imaging of HCV infection of polarized hepatoma spheroids, we observed that EGFR performs multiple functions in HCV entry, both phosphorylation-dependent and -independent. We previously observed, and in this study confirmed, that EGFR is not required for HCV migration to the tight junction. EGFR is required for the recruitment of clathrin to HCV in a phosphorylation-independent manner. EGFR phosphorylation is required for virion internalization at a stage following the recruitment of clathrin. HCV entry activates the RAF-MEK-ERK signaling pathway downstream of EGFR phosphorylation. This signaling pathway regulates the sorting and maturation of internalized HCV into APPL1- and EEA1-associated early endosomes, which form the site of virion uncoating. The tight junction proteins, CLDN1 and OCLN, function at two distinct stages of HCV entry. Despite its appreciated function as a "late receptor" in HCV entry, CLDN1 is required for efficient HCV virion accumulation at the tight junction. Huh-7.5 cells lacking CLDN1 accumulate HCV virions primarily at the initial basolateral surface. OCLN is required for the late stages of virion internalization. This study produced further insight into the unusually complex HCV endocytic process.
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Affiliation(s)
- Chui-Wa So
- Department of Microbiology, The University of Chicago, Chicago, Illinois, United States of America
| | - Marion Sourisseau
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Shamila Sarwar
- Department of Microbiology, The University of Chicago, Chicago, Illinois, United States of America
| | - Matthew J. Evans
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America
| | - Glenn Randall
- Department of Microbiology, The University of Chicago, Chicago, Illinois, United States of America
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19
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Lamothe-Reyes Y, Figueroa M, Sánchez O. Host cell factors involved in classical swine fever virus entry. Vet Res 2023; 54:115. [PMID: 38041163 PMCID: PMC10693020 DOI: 10.1186/s13567-023-01238-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/03/2023] [Indexed: 12/03/2023] Open
Abstract
Classical swine fever virus (CSFV) is an ancient pathogen that continues to pose a threat to animal agriculture worldwide. The virus belongs to the genus Pestivirus and the family Flaviviridae. It causes a multisystemic disease that affects only pigs and is responsible for significant economic losses. CSFV infection is probably a multistep process that involves the proteins in the virus envelope and more than one receptor in the membrane of permissive cells. To date, the cellular receptors essential for CSFV entry and their detailed functions during this process remains unknown. All the viral envelope proteins Erns, E1 and E2 are involved in the entry process to some extent and the experimental approaches conducted until now have helped to unveil their contributions. This review aims to provide an overview of current knowledge on cellular molecules described to be involved in CSFV entry, including complement regulatory protein 46 (CD46), heparan sulphate (HS), Laminin receptor, Integrin ß3, Annexin II, MERKT and ADAM17. This knowledge would not only help to understand the molecular mechanisms involved in pestivirus infection, but also provide a rational basis for the development of nonvaccinal alternatives for CSFV control.
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Affiliation(s)
- Yaneysis Lamothe-Reyes
- Laboratory of Molecular Biophysics, Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile.
- Laboratory of Recombinant Biopharmaceuticals, Department of Pharmacology, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile.
| | - Maximiliano Figueroa
- Laboratory of Molecular Biophysics, Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile
| | - Oliberto Sánchez
- Laboratory of Recombinant Biopharmaceuticals, Department of Pharmacology, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile.
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20
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Carriquí-Madroñal B, Sheldon J, Duven M, Stegmann C, Cirksena K, Wyler E, Zapatero-Belinchón FJ, Vondran FWR, Gerold G. The matrix metalloproteinase ADAM10 supports hepatitis C virus entry and cell-to-cell spread via its sheddase activity. PLoS Pathog 2023; 19:e1011759. [PMID: 37967063 PMCID: PMC10650992 DOI: 10.1371/journal.ppat.1011759] [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: 03/14/2023] [Accepted: 10/16/2023] [Indexed: 11/17/2023] Open
Abstract
Hepatitis C virus (HCV) exploits the four entry factors CD81, scavenger receptor class B type I (SR-BI, also known as SCARB1), occludin, and claudin-1 as well as the co-factor epidermal growth factor receptor (EGFR) to infect human hepatocytes. Here, we report that the disintegrin and matrix metalloproteinase 10 (ADAM10) associates with CD81, SR-BI, and EGFR and acts as HCV host factor. Pharmacological inhibition, siRNA-mediated silencing and genetic ablation of ADAM10 reduced HCV infection. ADAM10 was dispensable for HCV replication but supported HCV entry and cell-to-cell spread. Substrates of the ADAM10 sheddase including epidermal growth factor (EGF) and E-cadherin, which activate EGFR family members, rescued HCV infection of ADAM10 knockout cells. ADAM10 did not influence infection with other enveloped RNA viruses such as alphaviruses and a common cold coronavirus. Collectively, our study reveals a critical role for the sheddase ADAM10 as a HCV host factor, contributing to EGFR family member transactivation and as a consequence to HCV uptake.
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Affiliation(s)
- Belén Carriquí-Madroñal
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany
| | - Julie Sheldon
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany
| | - Mara Duven
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany
| | - Cora Stegmann
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany
| | - Karsten Cirksena
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany
| | - Emanuel Wyler
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany
| | - Francisco J. Zapatero-Belinchón
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany
- Gladstone Institutes, San Francisco, California, United States of America
| | - Florian W. R. Vondran
- Department of General, Visceral and Transplant Surgery, Regenerative Medicine and Experimental Surgery, Hannover Medical School, Hannover, Germany
- German Center for Infection Research Partner Site Hannover-Braunschweig Hannover, Germany
| | - Gisa Gerold
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hanover, Germany
- Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany
- Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden
- Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden
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21
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Torices S, Daire L, Simon S, Naranjo O, Mendoza L, Teglas T, Fattakhov N, Adesse D, Toborek M. Occludin: a gatekeeper of brain Infection by HIV-1. Fluids Barriers CNS 2023; 20:73. [PMID: 37840143 PMCID: PMC10577960 DOI: 10.1186/s12987-023-00476-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 10/09/2023] [Indexed: 10/17/2023] Open
Abstract
Compromised structure and function of the blood-brain barrier (BBB) is one of the pathological hallmarks of brain infection by HIV-1. BBB damage during HIV-1 infection has been associated with modified expression of tight junction (TJ) proteins, including occludin. Recent evidence indicated occludin as a redox-sensitive, multifunctional protein that can act as both an NADH oxidase and influence cellular metabolism through AMPK kinase. One of the newly identified functions of occludin is its involvement in regulating HIV-1 infection. Studies suggest that occludin expression levels and the rate of HIV-1 infection share a reverse, bidirectional relationship; however, the mechanisms of this relationship are unclear. In this review, we describe the pathways involved in the regulation of HIV-1 infection by occludin. We propose that occludin may serve as a potential therapeutic target to control HIV-1 infection and to improve the lives of people living with HIV-1.
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Affiliation(s)
- Silvia Torices
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
| | - Leah Daire
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
| | - Sierra Simon
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
| | - Oandy Naranjo
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
| | - Luisa Mendoza
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
| | - Timea Teglas
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
| | - Nikolai Fattakhov
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
| | - Daniel Adesse
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA
- Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil
| | - Michal Toborek
- Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, 528E Gautier Bldg. 1011 NW 15th Street Miami, Miami, FL, 11336, USA.
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22
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Chaudhary P, Proulx J, Park IW. Ubiquitin-protein ligase E3A (UBE3A) mediation of viral infection and human diseases. Virus Res 2023; 335:199191. [PMID: 37541588 PMCID: PMC10430597 DOI: 10.1016/j.virusres.2023.199191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/06/2023]
Abstract
The Ubiquitin-protein ligase E3A, UBE3A, also known as E6-associated protein (E6-AP), is known to play an essential role in regulating the degradation of various proteins by transferring Ub from E2 Ub conjugating enzymes to the substrate proteins. Several studies indicate that UBE3A regulates the stabilities of key viral proteins in the virus-infected cells and, thereby, the infected virus-mediated diseases, even if it were reported that UBE3A participates in non-viral-related human diseases. Furthermore, mutations such as deletions and duplications in the maternally inherited gene in the brain cause human neurodevelopmental disorders such as Angelman syndrome (AS) and autism. It is also known that UBE3A functions as a transcriptional coactivator for the expression of steroid hormone receptors. These reports establish that UBE3A is distinguished by its multitudinous functions that are paramount to viral pathology and human diseases. This review is focused on molecular mechanisms for such intensive participation of UBE3A in disease formation and virus regulation.
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Affiliation(s)
- Pankaj Chaudhary
- Department of Microbiology, Immunology and Genetics, School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
| | - Jessica Proulx
- Department of Microbiology, Immunology and Genetics, School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
| | - In-Woo Park
- Department of Microbiology, Immunology and Genetics, School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
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23
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Carriquí-Madroñal B, Lasswitz L, von Hahn T, Gerold G. Genetic and pharmacological perturbation of hepatitis-C virus entry. Curr Opin Virol 2023; 62:101362. [PMID: 37678113 DOI: 10.1016/j.coviro.2023.101362] [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: 12/02/2022] [Revised: 06/30/2023] [Accepted: 08/08/2023] [Indexed: 09/09/2023]
Abstract
Hepatitis-C virus (HCV) chronically infects 58 million individuals worldwide with variable disease outcome. While a subfraction of individuals exposed to the virus clear the infection, the majority develop chronic infection if untreated. Another subfraction of chronically ill proceeds to severe liver disease. The underlying causes of this interindividual variability include genetic polymorphisms in interferon genes. Here, we review available data on the influence of genetic or pharmacological perturbation of HCV host dependency factors on the clinically observed interindividual differences in disease outcome. We focus on host factors mediating virus entry into human liver cells. We assess available data on genetic variants of the major entry factors scavenger receptor class-B type I, CD81, claudin-1, and occludin as well as pharmacological perturbation of these entry factors. We review cell culture experimental and clinical cohort study data and conclude that entry factor perturbation may contribute to disease outcome of hepatitis C.
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Affiliation(s)
- Belén Carriquí-Madroñal
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany
| | - Lisa Lasswitz
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany
| | - Thomas von Hahn
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; Department of Gastroenterology, Hepatology and Interventional Endoscopy, Asklepios Hospital Barmbek, Semmelweis University, Campus Hamburg, 22307 Hamburg, Germany
| | - Gisa Gerold
- Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hanover, Hanover, Germany; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hanover, Germany; Wallenberg Centre for Molecular Medicine (WCMM), Umeå University, Umeå, Sweden; Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden.
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24
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Zhang Y, Kinast V, Sheldon J, Frericks N, Todt D, Zimmer M, Caliskan N, Brown RJP, Steinmann E, Pietschmann T. Mouse Liver-Expressed Shiftless Is an Evolutionarily Conserved Antiviral Effector Restricting Human and Murine Hepaciviruses. Microbiol Spectr 2023; 11:e0128423. [PMID: 37341610 PMCID: PMC10433982 DOI: 10.1128/spectrum.01284-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/02/2023] [Indexed: 06/22/2023] Open
Abstract
Mice are refractory to infection with human-tropic hepatitis C virus (HCV), although distantly related rodent hepaciviruses (RHV) circulate in wild rodents. To investigate whether liver intrinsic host factors can exhibit broad restriction against these distantly related hepaciviruses, we focused on Shiftless (Shfl), an interferon (IFN)-regulated gene (IRG) which restricts HCV in humans. Unusually, and in contrast to selected classical IRGs, human and mouse SHFL orthologues (hSHFL and mSHFL, respectively) were highly expressed in hepatocytes in the absence of viral infection, weakly induced by IFN, and highly conserved at the amino acid level (>95%). Replication of both HCV and RHV subgenomic replicons was suppressed by ectopic expression of mSHFL in human or rodent hepatoma cell lines. Gene editing of endogenous mShfl in mouse liver tumor cells increased HCV replication and virion production. Colocalization of mSHFL protein with viral double-stranded RNA (dsRNA) intermediates was confirmed and could be ablated by mutational disruption of the SHFL zinc finger domain, concomitant with a loss of antiviral activity. In summary, these data point to an evolutionarily conserved function for this gene in humans and rodents: SHFL is an ancient antiviral effector which targets distantly related hepaciviruses via restriction of viral RNA replication. IMPORTANCE Viruses have evolved ways to evade or blunt innate cellular antiviral mechanisms within their cognate host species. However, these adaptations may fail when viruses infect new species and can therefore limit cross-species transmission. This may also prevent development of animal models for human-pathogenic viruses. HCV shows a narrow species tropism likely due to distinct human host factor usage and innate antiviral defenses limiting infection of nonhuman liver cells. Interferon (IFN)-regulated genes (IRGs) partially inhibit HCV infection of human cells by diverse mechanisms. Here, we show that mouse Shiftless (mSHFL), a protein that interferes with HCV replication factories, inhibits HCV replication and infection in human and mouse liver cells. We further report that the zinc finger domain of SHFL is important for viral restriction. These findings implicate mSHFL as a host factor that impairs HCV infection of mice and provide guidance for development of HCV animal models needed for vaccine development.
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Affiliation(s)
- Yudi Zhang
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Volker Kinast
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Department of Medical Microbiology and Virology, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| | - Julie Sheldon
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Nicola Frericks
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany
| | - Daniel Todt
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Matthias Zimmer
- Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Zentrum für Infektionsforschung (Helmholtz Centre for Infection Research), Würzburg, Germany
- University of Würzburg, Faculty of Medicine, Würzburg, Germany
| | - Neva Caliskan
- Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Zentrum für Infektionsforschung (Helmholtz Centre for Infection Research), Würzburg, Germany
- University of Würzburg, Faculty of Medicine, Würzburg, Germany
| | - Richard J. P. Brown
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Division of Veterinary Medicine, Paul Ehrlich Institute, Langen, Germany
| | - Eike Steinmann
- Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Thomas Pietschmann
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany
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25
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Toon K, Kalemera MD, Palor M, Rose NJ, Takeuchi Y, Grove J, Mattiuzzo G. GB Virus B and Hepatitis C Virus, Distantly Related Hepaciviruses, Share an Entry Factor, Claudin-1. J Virol 2023; 97:e0046923. [PMID: 37310242 PMCID: PMC10373534 DOI: 10.1128/jvi.00469-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/10/2023] [Indexed: 06/14/2023] Open
Abstract
Due to increased and broadened screening efforts, the last decade has seen a rapid expansion in the number of viral species classified into the Hepacivirus genus. Conserved genetic features of hepaciviruses suggest that they have undergone specific adaptation and have evolved to hijack similar host proteins for efficient propagation in the liver. Here, we developed pseudotyped viruses to elucidate the entry factors of GB virus B (GBV-B), the first hepacivirus described in an animal after hepatitis C virus (HCV). GBV-B-pseudotyped viral particles (GBVBpp) were shown to be uniquely sensitive to the sera of tamarins infected with GBV-B, validating their usefulness as a surrogate for GBV-B entry studies. We screened GBVBpp infection of human hepatoma cell lines that were CRISPR/Cas9 engineered to ablate the expression of individual HCV receptors/entry factors and found that claudin-1 is essential for GBV-B infection, indicating the GBV-B and HCV share an entry factor. Our data suggest that claudin-1 facilitates HCV and GBV-B entry through distinct mechanisms since the former requires the first extracellular loop and the latter is reliant on a C-terminal region containing the second extracellular loop. The observation that claudin-1 is an entry factor shared between these two hepaciviruses suggests that the tight junction protein is of fundamental mechanistic importance during cell entry. IMPORTANCE Hepatitis C virus (HCV) is a major public health burden; approximately 58 million individuals have chronic HCV infection and are at risk of developing cirrhosis and liver cancer. To achieve the World Health Organization's target of eliminating hepatitis by 2030, new therapeutics and vaccines are needed. Understanding how HCV enters cells can inform the design of new vaccines and treatments targeting the first stage of infection. However, the HCV cell entry mechanism is complex and has been sparsely described. Studying the entry of related hepaciviruses will increase the knowledge of the molecular mechanisms of the first stages of HCV infection, such as membrane fusion, and inform structure-guided HCV vaccine design; in this work, we have identified a protein, claudin-1, that facilitates the entry of an HCV-related hepacivirus but with a mechanism not described for HCV. Similar work on other hepaciviruses may unveil a commonality of entry factors and, possibly, new mechanisms.
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Affiliation(s)
- Kamilla Toon
- Science Research and Innovation, Medicines and Healthcare Products Regulatory Agency, South Mimms, United Kingdom
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Mphatso D. Kalemera
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Machaela Palor
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Nicola J. Rose
- Science Research and Innovation, Medicines and Healthcare Products Regulatory Agency, South Mimms, United Kingdom
| | - Yasuhiro Takeuchi
- Science Research and Innovation, Medicines and Healthcare Products Regulatory Agency, South Mimms, United Kingdom
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Joe Grove
- Division of Infection and Immunity, University College London, London, United Kingdom
- MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
| | - Giada Mattiuzzo
- Science Research and Innovation, Medicines and Healthcare Products Regulatory Agency, South Mimms, United Kingdom
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26
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Ströh LJ, Krey T. Structural insights into hepatitis C virus neutralization. Curr Opin Virol 2023; 60:101316. [DOI: 10.1016/j.coviro.2023.101316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/12/2023] [Indexed: 03/31/2023]
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27
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Zhang J, Yang W, Roy S, Liu H, Roberts R, Wang L, Shi L, Ma W. Tight junction protein occludin is an internalization factor for SARS-CoV-2 infection and mediates virus cell-to-cell transmission. Proc Natl Acad Sci U S A 2023; 120:e2218623120. [PMID: 37068248 PMCID: PMC10151465 DOI: 10.1073/pnas.2218623120] [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: 10/31/2022] [Accepted: 03/13/2023] [Indexed: 04/19/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads efficiently by spike-mediated, direct cell-to-cell transmission. However, the underlying mechanism is poorly understood. Herein, we demonstrate that the tight junction protein occludin (OCLN) is critical to this process. SARS-CoV-2 infection alters OCLN distribution and expression and causes syncytium formation that leads to viral spread. OCLN knockdown fails to alter SARS-CoV-2 binding but significantly lowers internalization, syncytium formation, and transmission. OCLN overexpression also has no effect on virus binding but enhances virus internalization, cell-to-cell transmission, and replication. OCLN directly interacts with the SARS-CoV-2 spike, and the endosomal entry pathway is involved in OCLN-mediated cell-to-cell fusion rather than in the cell surface entry pathway. All SARS-CoV-2 strains tested (prototypic, alpha, beta, gamma, delta, kappa, and omicron) are dependent on OCLN for cell-to-cell transmission, although the extent of syncytium formation differs between strains. We conclude that SARS-CoV-2 utilizes OCLN as an internalization factor for cell-to-cell transmission.
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Affiliation(s)
- Jialin Zhang
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO65211
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO65211
| | - Wenyu Yang
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO65211
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO65211
| | - Sawrab Roy
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO65211
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO65211
| | - Heidi Liu
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO65211
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO65211
| | - R. Michael Roberts
- Division of Animal Sciences, College of Agriculture, Food, & Natural Resources, University of Missouri, Columbia, MO65211
- Christopher S Bond Life Sciences Center, University of Missouri, Columbia, MO65211
| | - Liping Wang
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO65211
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO65211
| | - Lei Shi
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO65211
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO65211
| | - Wenjun Ma
- Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO65211
- Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO65211
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28
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Jabin A, Uddin MF, Al Azad S, Rahman A, Tabassum F, Sarker P, Morshed AKMH, Rahman S, Raisa FF, Sakib MR, Olive AH, Islam T, Tahsin R, Ahmed SZ, Biswas P, Habiba MU, Siddiquy M, Jafary M. Target-specificity of different amyrin subunits in impeding HCV influx mechanism inside the human cells considering the quantum tunnel profiles and molecular strings of the CD81 receptor: a combined in silico and in vivo study. In Silico Pharmacol 2023; 11:8. [PMID: 36999133 PMCID: PMC10052254 DOI: 10.1007/s40203-023-00144-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 02/11/2023] [Indexed: 03/31/2023] Open
Abstract
HCV is a hepatotropic RNA virus recognized for its frequent virulence and fatality worldwide. Despite many vaccine development programs underway, researchers are on a quest for natural bioactive compounds due to their multivalent efficiencies against viral infections, considering which the current research aimed to figure out the target-specificity and therapeutic potentiality of α, β, and δ subunits of amyrin, as novel bioactive components against the HCV influx mechanism. Initially, the novelty of amyrin subunits was conducted from 203 pharmacophores, comparing their in-silico pharmacokinetic and pharmacodynamic profiles. Besides, the best active site of CD81 was determined following the quantum tunneling algorithm. The molecular dynamic simulation was conducted (100 ns) following the molecular docking steps to reveal the parameters- RMSD (Å); Cα; RMSF (Å); MolSA (Å2); Rg (nm); PSA (Å); SASA (Å2), and the MM-GBSA dG binding scores. Besides, molecular strings of CD81, along with the co-expressed genes, were classified, as responsible for encoding CD81-mediated protein clusters during HCV infection, resulting in the potentiality of amyrins as targeted prophylactics in HCV infection. Finally, in vivo profiling of the oxidative stress marker, liver-specific enzymes, and antioxidant markers was conducted in the DMN-induced mice model, where β-amyrin scored the most significant values in all aspects.
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Affiliation(s)
- Anika Jabin
- grid.443020.10000 0001 2295 3329Department of Biochemistry and Microbiology, North South University, Dhaka, 1229 Bangladesh
| | - Mohammad Fahim Uddin
- grid.413273.00000 0001 0574 8737College of Material Science and Engineering, Zhejiang Sci-Tech University, Hangzhou, 310018 Zhejiang People’s Republic of China
| | - Salauddin Al Azad
- grid.258151.a0000 0001 0708 1323Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, 214122 Jiangsu Province People’s Republic of China
| | - Ashfaque Rahman
- grid.443020.10000 0001 2295 3329Department of Biochemistry and Microbiology, North South University, Dhaka, 1229 Bangladesh
| | - Fawzia Tabassum
- grid.412506.40000 0001 0689 2212Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet, 3114 Bangladesh
| | - Pritthy Sarker
- grid.443020.10000 0001 2295 3329Department of Biochemistry and Microbiology, North South University, Dhaka, 1229 Bangladesh
| | - A K M Helal Morshed
- grid.207374.50000 0001 2189 3846Pathology and Pathophysiology Major, Academy of Medical Science, Zhengzhou University, Zhengzhou City, 450001 Henan Province People’s Republic of China
| | - Samiur Rahman
- grid.443020.10000 0001 2295 3329Department of Biochemistry and Microbiology, North South University, Dhaka, 1229 Bangladesh
| | - Fatima Fairuz Raisa
- grid.52681.380000 0001 0746 8691Department of Electrical and Electronic Engineering, Brac University, Dhaka, 1212 Bangladesh
| | - Musfiqur Rahman Sakib
- grid.449329.10000 0004 4683 9733Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100 Bangladesh
| | - Abeer Hasan Olive
- grid.442996.40000 0004 0451 6987Department of Pharmacy, East West University, Dhaka, 1212 Bangladesh
| | - Tabassum Islam
- grid.442996.40000 0004 0451 6987Department of Computer Science and Engineering, East West University, Dhaka, 1212 Bangladesh
| | - Ramisha Tahsin
- grid.443020.10000 0001 2295 3329Department of Pharmaceutical Sciences, North South University, Dhaka, 1229 Bangladesh
| | - Shahlaa Zernaz Ahmed
- grid.443020.10000 0001 2295 3329Department of Biochemistry and Microbiology, North South University, Dhaka, 1229 Bangladesh
| | - Partha Biswas
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408 Bangladesh
| | - Mst. Umme Habiba
- Data Science Research Unit, RPG Interface Lab, Jashore, 7400 Bangladesh
| | - Mahbuba Siddiquy
- grid.258151.a0000 0001 0708 1323State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, 214122 Jiangsu Province People’s Republic of China
| | - Maryam Jafary
- grid.411705.60000 0001 0166 0922Division of Food Safety and Hygiene, Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, 1416634793 Iran
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Kumar A, Rohe TC, Elrod EJ, Khan AG, Dearborn AD, Kissinger R, Grakoui A, Marcotrigiano J. Regions of hepatitis C virus E2 required for membrane association. Nat Commun 2023; 14:433. [PMID: 36702826 PMCID: PMC9879980 DOI: 10.1038/s41467-023-36183-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
Hepatitis C virus (HCV) uses a hybrid entry mechanism. Current structural data suggest that upon exposure to low pH and Cluster of Differentiation 81 (CD81), the amino terminus of envelope glycoprotein E2 becomes ordered and releases an internal loop with two invariant aromatic residues into the host membrane. Here, we present the structure of an amino-terminally truncated E2 with the membrane binding loop in a bent conformation and the aromatic side chains sequestered. Comparison with three previously reported E2 structures with the same Fab indicates that this internal loop is flexible, and that local context influences the exposure of hydrophobic residues. Biochemical assays show that the amino-terminally truncated E2 lacks the baseline membrane-binding capacity of the E2 ectodomain. Thus, the amino terminal region is a critical determinant for both CD81 and membrane interaction. These results provide new insights into the HCV entry mechanism.
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Affiliation(s)
- Ashish Kumar
- Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tiana C Rohe
- Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Elizabeth J Elrod
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30329, USA
| | - Abdul G Khan
- Center for Advanced Biotechnology and Medicine, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
| | - Altaira D Dearborn
- Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ryan Kissinger
- Research Technology Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA
| | - Arash Grakoui
- Emory National Primate Research Center, Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, 30329, USA
| | - Joseph Marcotrigiano
- Structural Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
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30
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Ju X, Dong L, Ding Q. Hepatitis E Virus Life Cycle. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:141-157. [PMID: 37223864 DOI: 10.1007/978-981-99-1304-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) infects over 20 million people worldwide per year, leading to 30,000-40,000 deaths. In most cases HEV infection in a self-limited, acute illness. However, chronic infections could occur in immunocompromised individuals. Due to scarcity of robust cell culture models in vitro and genetic tractable animal models in vivo, the details of HEV life cycle, as well as its interaction with host cells still remain elusive, which dampens antivirals discovery. In this chapter, we present an update in the HEV infectious cycle steps: entry, genome replication/subgenomic RNA transcription, assembly, and release. Moreover, we discussed the future prospective on HEV research and illustrates important questions urgently to be addressed.
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Affiliation(s)
- Xiaohui Ju
- School of Medicine, Tsinghua University, Beijing, China
| | - Lin Dong
- School of Medicine, Tsinghua University, Beijing, China
| | - Qiang Ding
- School of Medicine, Tsinghua University, Beijing, China.
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31
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Mechanisms and Consequences of Genetic Variation in Hepatitis C Virus (HCV). Curr Top Microbiol Immunol 2023; 439:237-264. [PMID: 36592248 DOI: 10.1007/978-3-031-15640-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Chronic infection with hepatitis C virus (HCV) is an important contributor to the global incidence of liver diseases, including liver cirrhosis and hepatocellular carcinoma. Although common for single-stranded RNA viruses, HCV displays a remarkable high level of genetic diversity, produced primarily by the error-prone viral polymerase and host immune pressure. The high genetic heterogeneity of HCV has led to the evolution of several distinct genotypes and subtypes, with important consequences for pathogenesis, and clinical outcomes. Genetic variability constitutes an evasion mechanism against immune suppression, allowing the virus to evolve epitope escape mutants that avoid immune recognition. Thus, heterogeneity and variability of the HCV genome represent a great hindrance for the development of vaccines against HCV. In addition, the high genetic plasticity of HCV allows the virus to rapidly develop antiviral resistance mutations, leading to treatment failure and potentially representing a major hindrance for the cure of chronic HCV patients. In this chapter, we will present the central role that genetic diversity has in the viral life cycle and epidemiology of HCV. Incorporation errors and recombination, both the result of HCV polymerase activity, represent the main mechanisms of HCV evolution. The molecular details of both mechanisms have been only partially clarified and will be presented in the following sections. Finally, we will discuss the major consequences of HCV genetic diversity, namely its capacity to rapidly evolve antiviral and immunological escape variants that represent an important limitation for clearance of acute HCV, for treatment of chronic hepatitis C and for broadly protective vaccines.
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32
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Zhang R. Studying Virus-Host Interactions with CRISPR Technology. Methods Mol Biol 2023; 2585:105-117. [PMID: 36331769 DOI: 10.1007/978-1-0716-2760-0_11] [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: 06/16/2023]
Abstract
The mosquito-borne West Nile virus (WNV) poses a great threat to public health as no vaccine or specific antiviral treatment is available. Exploring virus-host interactions, specifically host factors that are required for virus infection, is important for better understanding the biology, pathogenesis, and transmission of WNV. Such essential host factors may also represent antiviral targets. The development of CRISPR technology has provided a powerful and convenient tool to perturbate host gene expression, allowing for unbiased, genome-wide screens of host factors for virus infection. Here we describe the necessary steps for performing a CRISPR knockout screen, which can also be applied to other viruses, to identify host factors critical for WNV infection.
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Affiliation(s)
- Rong Zhang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
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33
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Butt F, Shahid M, Hassan M, Tawakkal F, Amin I, Afzal S, Bhatti R, Nawaz R, Idrees M. A review on hepatitis C virus: role of viral and host-cellular factors in replication and existing therapeutic strategies. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00232-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Abstract
Background
Hepatitis C virus, a member of Flaviviridae is a single-stranded positive-sense RNA virus infecting 62–79 million people around the globe. This blood-borne virus is one of the leading causes of liver diseases worldwide. This review aims to identify novel potential genes linked to cellular host factors, as well as revise the roles of each gene in hepatitis C Virus infection. This review also aims to provide a comprehensive insight into therapeutic advancements against HCV.
Methods
For this review article, 190 articles were searched via PubMed Central, Bio-One, National Academy of Science, Google Scholar, and Worldwide Science. 0ut of these 190 studies, 55 articles were selected for this review. The inclusion of articles was done on the criteria of high citation and Q1 ranking.
Results
The information gathered from previously published articles highlighted a critical link between host-cellular factors that are important for HCV infection.
Conclusion
Although many advancements in HCV treatment have been made like DAAs and HTAs, the development of a completely effective HCV therapy is still a challenge. Further research on combinations of DAAs and HTAs can help in developing a better therapeutic alternative. Keywords: Hepatitis C virus, Replication cycle, Non-structural proteins, Host-cellular factors, Treatment strategies
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A single mutation in the E2 glycoprotein of hepatitis C virus broadens the claudin specificity for its infection. Sci Rep 2022; 12:20243. [PMID: 36424447 PMCID: PMC9691748 DOI: 10.1038/s41598-022-23824-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 11/07/2022] [Indexed: 11/27/2022] Open
Abstract
Entry of the hepatitis C virus (HCV) into host cells is a multistep process mediated by several host factors, including a tight junction protein claudin-1 (CLDN1). We repeatedly passaged HCV-JFH1-tau, an HCV substrain with higher infectivity, on Huh7.5.1-8 cells. A multi-passaged HCV-JFH1-tau lot was infectious to CLDN1-defective S7-A cells, non-permissive to original HCV-JFH1-tau infection. We identified a single mutation, M706L, in the E2 glycoprotein of the HCV-JFH1-tau lot as an essential mutation for infectivity to S7-A cells. The pseudovirus JFH1/M706L mutant could not infect human embryonic kidney 293 T (HEK293T) cells lacking CLDN family but infected HEK293T cells expressing CLDN1, CLDN6, or CLDN9. Thus, this mutant virus could utilize CLDN1, and other CLDN6 and CLDN9, making HCV possible to infect cells other than hepatocytes. iPS cells, one of the stem cells, do not express CLDN1 but express CLDN6 and other host factors required for HCV infection. We confirmed that the HCV-JFH1-tau-derived mutant with an M706L mutation infected iPS cells in a CLDN6-dependent manner. These results demonstrated that a missense mutation in E2 could broaden the CLDN member specificity for HCV infection. HCV may change its receptor requirement through a single amino acid mutation and infect non-hepatic cells.
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35
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Zhang Y, Chen Y, Zhou J, Wang X, Ma L, Li J, Yang L, Yuan H, Pang D, Ouyang H. Porcine Epidemic Diarrhea Virus: An Updated Overview of Virus Epidemiology, Virulence Variation Patterns and Virus-Host Interactions. Viruses 2022; 14:2434. [PMID: 36366532 PMCID: PMC9695474 DOI: 10.3390/v14112434] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
The porcine epidemic diarrhea virus (PEDV) is a member of the coronavirus family, causing deadly watery diarrhea in newborn piglets. The global pandemic of PEDV, with significant morbidity and mortality, poses a huge threat to the swine industry. The currently developed vaccines and drugs are only effective against the classic GI strains that were prevalent before 2010, while there is no effective control against the GII variant strains that are currently a global pandemic. In this review, we summarize the latest progress in the biology of PEDV, including its transmission and origin, structure and function, evolution, and virus-host interaction, in an attempt to find the potential virulence factors influencing PEDV pathogenesis. We conclude with the mechanism by which PEDV components antagonize the immune responses of the virus, and the role of host factors in virus infection. Essentially, this review serves as a valuable reference for the development of attenuated virus vaccines and the potential of host factors as antiviral targets for the prevention and control of PEDV infection.
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Affiliation(s)
- Yuanzhu Zhang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Yiwu Chen
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Jian Zhou
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Xi Wang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Lerong Ma
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Jianing Li
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Lin Yang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
| | - Hongming Yuan
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
- Chongqing Research Institute, Jilin University, Chongqing 401120, China
| | - Daxin Pang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
- Chongqing Research Institute, Jilin University, Chongqing 401120, China
- Chongqing Jitang Biotechnology Research Institute Co., Ltd., Chongqing 401120, China
| | - Hongsheng Ouyang
- Key Laboratory of Zoonosis Research, Ministry of Education, College of Animal Sciences, Jilin University, Changchun 130062, China
- Chongqing Research Institute, Jilin University, Chongqing 401120, China
- Chongqing Jitang Biotechnology Research Institute Co., Ltd., Chongqing 401120, China
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36
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Wolfisberg R, Thorselius CE, Salinas E, Elrod E, Trivedi S, Nielsen L, Fahnøe U, Kapoor A, Grakoui A, Rice CM, Bukh J, Holmbeck K, Scheel TKH. Neutralization and receptor use of infectious culture-derived rat hepacivirus as a model for HCV. Hepatology 2022; 76:1506-1519. [PMID: 35445423 PMCID: PMC9585093 DOI: 10.1002/hep.32535] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS Lack of tractable immunocompetent animal models amenable to robust experimental challenge impedes vaccine efforts for HCV. Infection with rodent hepacivirus from Rattus norvegicus (RHV-rn1) in rats shares HCV-defining characteristics, including liver tropism, chronicity, and pathology. RHV in vitro cultivation would facilitate genetic studies on particle production, host factor interactions, and evaluation of antibody neutralization guiding HCV vaccine approaches. APPROACH AND RESULTS We report an infectious reverse genetic cell culture system for RHV-rn1 using highly permissive rat hepatoma cells and adaptive mutations in the E2, NS4B, and NS5A viral proteins. Cell culture-derived RHV-rn1 particles (RHVcc) share hallmark biophysical characteristics of HCV and are infectious in mice and rats. Culture adaptive mutations attenuated RHVcc in immunocompetent rats, and the mutations reverted following prolonged infection, but not in severe combined immunodeficiency (SCID) mice, suggesting that adaptive immune pressure is a primary driver of reversion. Accordingly, sera from RHVcc-infected SCID mice or the early acute phase of immunocompetent mice and rats were infectious in culture. We further established an in vitro RHVcc neutralization assay, and observed neutralizing activity of rat sera specifically from the chronic phase of infection. Finally, we found that scavenger receptor class B type I promoted RHV-rn1 entry in vitro and in vivo. CONCLUSIONS The RHV-rn1 infectious cell culture system enables studies of humoral immune responses against hepacivirus infection. Moreover, recapitulation of the entire RHV-rn1 infectious cycle in cell culture will facilitate reverse genetic studies and the exploration of tropism and virus-host interactions.
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Affiliation(s)
- Raphael Wolfisberg
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Caroline E. Thorselius
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Eduardo Salinas
- Emory Vaccine CenterDivision of Microbiology and ImmunologyYerkes Research Primate CenterEmory University School of MedicineAtlantaGeorgiaUSA,Division of Infectious DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGeorgiaUSA
| | - Elizabeth Elrod
- Emory Vaccine CenterDivision of Microbiology and ImmunologyYerkes Research Primate CenterEmory University School of MedicineAtlantaGeorgiaUSA,Division of Infectious DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGeorgiaUSA
| | - Sheetal Trivedi
- Center for Vaccines and ImmunityResearch Institute at Nationwide Children’s HospitalColumbusOhioUSA
| | - Louise Nielsen
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Ulrik Fahnøe
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Amit Kapoor
- Center for Vaccines and ImmunityResearch Institute at Nationwide Children’s HospitalColumbusOhioUSA
| | - Arash Grakoui
- Emory Vaccine CenterDivision of Microbiology and ImmunologyYerkes Research Primate CenterEmory University School of MedicineAtlantaGeorgiaUSA,Division of Infectious DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGeorgiaUSA
| | - Charles M. Rice
- Laboratory of Virology and Infectious DiseaseThe Rockefeller UniversityNew YorkNew YorkUSA
| | - Jens Bukh
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Kenn Holmbeck
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
| | - Troels K. H. Scheel
- Copenhagen Hepatitis C ProgramDepartment of Infectious DiseasesHvidovre HospitalCopenhagenDenmark,Department of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark,Laboratory of Virology and Infectious DiseaseThe Rockefeller UniversityNew YorkNew YorkUSA
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37
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Deffieu MS, Clément CMH, Dorobantu CM, Partiot E, Bare Y, Faklaris O, Rivière B, Ayala-Nunez NV, Baumert TF, Rondé P, Mély Y, Lucansky V, Gaudin R. Occludin stalls HCV particle dynamics apart from hepatocyte tight junctions, promoting virion internalization. Hepatology 2022; 76:1164-1179. [PMID: 35388524 DOI: 10.1002/hep.32514] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 03/28/2022] [Accepted: 04/03/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS Numerous HCV entry factors have been identified, and yet information regarding their spatiotemporal dynamics is still limited. Specifically, one of the main entry factors of HCV is occludin (OCLN), a protein clustered at tight junctions (TJs), away from the HCV landing site. Thus, whether HCV particles slide toward TJs or, conversely, OCLN is recruited away from TJs remain debated. APPROACH AND RESULTS Here, we generated CRISPR/CRISPR-associated protein 9 edited Huh7.5.1 cells expressing endogenous levels of enhanced green fluorescent protein/OCLN and showed that incoming HCV particles recruit OCLN outside TJs, independently of claudin 1 (CLDN1) expression, another important HCV entry factor located at TJs. Using ex vivo organotypic culture of hepatic slices obtained from human liver explants, a physiologically relevant model that preserves the overall tissue architecture, we confirmed that HCV associates with OCLN away from TJs. Furthermore, we showed, by live cell imaging, that increased OCLN recruitment beneath HCV particles correlated with lower HCV motility. To decipher the mechanism underlying virus slow-down upon OCLN recruitment, we performed CRISPR knockout (KO) of CLDN1, an HCV entry factor proposed to act upstream of OCLN. Although CLDN1 KO potently inhibits HCV infection, OCLN kept accumulating underneath the particle, indicating that OCLN recruitment is CLDN1 independent. Moreover, inhibition of the phosphorylation of Ezrin, a protein involved in HCV entry that links receptors to the actin cytoskeleton, increased OCLN accumulation and correlated with more efficient HCV internalization. CONCLUSIONS Together, our data provide robust evidence that HCV particles interact with OCLN away from TJs and shed mechanistic insights regarding the manipulation of transmembrane receptor localization by extracellular virus particles.
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Affiliation(s)
- Maika S Deffieu
- 27051Institut de Recherche en infectiologie de Montpellier (IRIM)CNRSMontpellierFrance
- Université de MontpellierMontpellierFrance
| | - Camille M H Clément
- 27051Institut de Recherche en infectiologie de Montpellier (IRIM)CNRSMontpellierFrance
- Université de MontpellierMontpellierFrance
- Université de StrasbourgStrasbourgFrance
- INSERMInstitut de Recherche sur les Maladies Virales et HépatiquesStrasbourgFrance
| | - Cristina M Dorobantu
- Université de StrasbourgStrasbourgFrance
- INSERMInstitut de Recherche sur les Maladies Virales et HépatiquesStrasbourgFrance
- Janssen Vaccines and Prevention B.V. Newtonweg 12333 CP Leiden PO Box 20482301CA LeidenThe Netherlands
| | - Emma Partiot
- 27051Institut de Recherche en infectiologie de Montpellier (IRIM)CNRSMontpellierFrance
- Université de MontpellierMontpellierFrance
| | - Yonis Bare
- 27051Institut de Recherche en infectiologie de Montpellier (IRIM)CNRSMontpellierFrance
- Université de MontpellierMontpellierFrance
| | | | - Benjamin Rivière
- CHU MontpellierLaboratoire d'Anatomie et Cytologie Pathologiques-CRBMontpellierFrance
| | - Nilda Vanesa Ayala-Nunez
- 27051Institut de Recherche en infectiologie de Montpellier (IRIM)CNRSMontpellierFrance
- Université de MontpellierMontpellierFrance
- Empa-Swiss Federal Laboratories for Materials Science and Technology. Lerchenfeldstrasse 59014St. GallenSwitzerland
| | - Thomas F Baumert
- Université de StrasbourgStrasbourgFrance
- INSERMInstitut de Recherche sur les Maladies Virales et HépatiquesStrasbourgFrance
- Pole Hépato-digestifHôpitaux Universitaires de StrasbourgInstitut Hospitalo-universitaireStrasbourgFrance
| | - Philippe Rondé
- Université de StrasbourgStrasbourgFrance
- UMR 7021 CNRSLaboratoire de Bioimagerie et PathologiesUniversité de StrasbourgFaculté de pharmacieIllkirchFrance
| | - Yves Mély
- Université de StrasbourgStrasbourgFrance
- UMR 7021 CNRSLaboratoire de Bioimagerie et PathologiesUniversité de StrasbourgFaculté de pharmacieIllkirchFrance
| | - Vincent Lucansky
- Université de StrasbourgStrasbourgFrance
- INSERMInstitut de Recherche sur les Maladies Virales et HépatiquesStrasbourgFrance
- Comenius University in Bratislavathe Jessenius Faculty of Medicine in Martin (JFMED CU)Biomedical Center MartinMala Hora 4C036 01MartinSlovakia
| | - Raphael Gaudin
- 27051Institut de Recherche en infectiologie de Montpellier (IRIM)CNRSMontpellierFrance
- Université de MontpellierMontpellierFrance
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38
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Schwoerer MP, Ploss A. Barriers to hepatitis C virus infection in mice. Curr Opin Virol 2022; 56:101273. [PMID: 36244239 DOI: 10.1016/j.coviro.2022.101273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/14/2022] [Indexed: 11/29/2022]
Abstract
Hepatitis C virus (HCV) is unable to infect mice, a fact that has severely limited their use as small-animal models for HCV pathogenesis and as tools for HCV vaccine development. HCV is blocked at various stages of its life cycle in mouse cells, due to incompatibility with host factors, the presence of dominant restriction factors, and effective immune responses. Molecular mechanisms for several such blocks have been characterized. The stepwise understanding of these limitations in mice will enable the development of an immunocompetent mouse that can fully support HCV infection and exhibit disease similar to that of infected humans.
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Affiliation(s)
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
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39
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Suhail M, Sohrab SS, Kamal M, Azhar EI. Role of hepatitis c virus in hepatocellular carcinoma and neurological disorders: an overview. Front Oncol 2022; 12:913231. [PMID: 35965577 PMCID: PMC9372299 DOI: 10.3389/fonc.2022.913231] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
The hepatitis C virus (HCV) causes serious issues, affecting 71 million people globally. The most common manifestations range from chronic hepatitis to liver cirrhosis, leading to hepatocellular carcinoma. Many mechanisms are known to play an important role in HCV-induced HCC. The interaction of viral proteins with host cells results in oxidative stress damage, liver inflammation, and irregularities in signaling pathways. These results in the activation of oncogenes and metabolic disturbances, liver fibrosis, and angiogenesis. Additionally, some non-coding RNAs (ncRNAs) and toll-like receptors have been identified and play a significant role in HCC development. This virus is also associated with impairment of the central nervous system, resulting in acute or sub-acute encephalopathy and inflammatory disorders. Neurological disorders are associated with the inflammatory responses of many cells, including microglia and astrocytes. Additionally, there are many other extrahepatic manifestations, including neurological disorders such as depression and fatigue, in 50% of infected patients. These manifestations include neuro-invasion, immune-mediated damage, neurotransmitter alterations, sensory-motor polyneuropathy, sensitivity loss, weakness of the leg, and cryoglobulinemia, which significantly results in a reduced quality of life. HCV infection may be improved using an appropriate diagnosis and direct antiviral therapy for sustained virological response. However, the success of therapy depends on the symptoms and organ damage, diagnosis, and therapeutic strategies applied. Some published reports have discussed that HCV is associated with both HCC and neurological disorders. Additionally, it has also been observed that individuals with HCC also develop neurological disorders compared with individuals with HCV alone. This review aims to provide an overview of the latest information about the relationship between HCV-induced HCC and their role in neurological disorders. Additionally, we have also discussed the progress made in the diagnosis, physio-pathological mechanisms, and strong antiviral therapies developed for HCV infection and HCC, as well as the latest advancements made in the study of the neurological disorders associated with HCV infection.
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Affiliation(s)
- Mohd Suhail
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sayed Sartaj Sohrab
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- *Correspondence: Sayed Sartaj Sohrab,
| | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- West China School of Nursing/Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- Enzymoics Novel Global Community Educational Foundation, Hebersham, NSW, Australia
| | - Esam Ibraheem Azhar
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
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40
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Stejskal L, Kalemera MD, Lewis CB, Palor M, Walker L, Daviter T, Lees WD, Moss DS, Kremyda-Vlachou M, Kozlakidis Z, Gallo G, Bailey D, Rosenberg W, Illingworth CJR, Shepherd AJ, Grove J. An entropic safety catch controls hepatitis C virus entry and antibody resistance. eLife 2022; 11:e71854. [PMID: 35796426 PMCID: PMC9333995 DOI: 10.7554/elife.71854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 06/28/2022] [Indexed: 11/24/2022] Open
Abstract
E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery.
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Affiliation(s)
- Lenka Stejskal
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College LondonLondonUnited Kingdom
- Institute of Structural and Molecular Biology, Birkbeck CollegeLondonUnited Kingdom
| | - Mphatso D Kalemera
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College LondonLondonUnited Kingdom
| | - Charlotte B Lewis
- MRC-University of Glasgow Centre for Virus ResearchGlasgowUnited Kingdom
| | - Machaela Palor
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College LondonLondonUnited Kingdom
| | - Lucas Walker
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College LondonLondonUnited Kingdom
| | - Tina Daviter
- Institute of Structural and Molecular Biology, Birkbeck CollegeLondonUnited Kingdom
- Shared Research Facilities, The Institute of Cancer ResearchLondonUnited Kingdom
| | - William D Lees
- Institute of Structural and Molecular Biology, Birkbeck CollegeLondonUnited Kingdom
| | - David S Moss
- Institute of Structural and Molecular Biology, Birkbeck CollegeLondonUnited Kingdom
| | | | - Zisis Kozlakidis
- International Agency for Research on Cancer, World Health OrganizationLyonFrance
| | | | | | - William Rosenberg
- Division of Medicine, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Christopher JR Illingworth
- MRC-University of Glasgow Centre for Virus ResearchGlasgowUnited Kingdom
- Department of Genetics, University of CambridgeCambridgeUnited Kingdom
- Institut für Biologische Physik, Universität zu KölnCologneGermany
- MRC Biostatistics Unit, University of CambridgeCambridgeUnited Kingdom
| | - Adrian J Shepherd
- Institute of Structural and Molecular Biology, Birkbeck CollegeLondonUnited Kingdom
| | - Joe Grove
- Institute of Immunity and Transplantation, Division of Infection and Immunity, University College LondonLondonUnited Kingdom
- MRC-University of Glasgow Centre for Virus ResearchGlasgowUnited Kingdom
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41
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Direct-Acting Antiviral Agents for Hepatitis C Virus Infection-From Drug Discovery to Successful Implementation in Clinical Practice. Viruses 2022; 14:v14061325. [PMID: 35746796 PMCID: PMC9231290 DOI: 10.3390/v14061325] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 12/13/2022] Open
Abstract
Today, hepatitis C virus infection affects up to 1.5 million people per year and is responsible for 29 thousand deaths per year. In the 1970s, the clinical observation of unclear, transfusion-related cases of hepatitis ignited scientific curiosity, and after years of intensive, basic research, the hepatitis C virus was discovered and described as the causative agent for these cases of unclear hepatitis in 1989. Even before the description of the hepatitis C virus, clinicians had started treating infected individuals with interferon. However, intense side effects and limited antiviral efficacy have been major challenges, shaping the aim for the development of more suitable and specific treatments. Before direct-acting antiviral agents could be developed, a detailed understanding of viral properties was necessary. In the years after the discovery of the new virus, several research groups had been working on the hepatitis C virus biology and finally revealed the replication cycle. This knowledge was the basis for the later development of specific antiviral drugs referred to as direct-acting antiviral agents. In 2011, roughly 22 years after the discovery of the hepatitis C virus, the first two drugs became available and paved the way for a revolution in hepatitis C therapy. Today, the treatment of chronic hepatitis C virus infection does not rely on interferon anymore, and the treatment response rate is above 90% in most cases, including those with unsuccessful pretreatments. Regardless of the clinical and scientific success story, some challenges remain until the HCV elimination goals announced by the World Health Organization are met.
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42
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Pfaff-Kilgore JM, Davidson E, Kadash-Edmondson K, Hernandez M, Rosenberg E, Chambers R, Castelli M, Clementi N, Mancini N, Bailey JR, Crowe JE, Law M, Doranz BJ. Sites of vulnerability in HCV E1E2 identified by comprehensive functional screening. Cell Rep 2022; 39:110859. [PMID: 35613596 PMCID: PMC9281441 DOI: 10.1016/j.celrep.2022.110859] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 12/08/2021] [Accepted: 05/01/2022] [Indexed: 12/15/2022] Open
Abstract
The E1 and E2 envelope proteins of hepatitis C virus (HCV) form a heterodimer that drives virus-host membrane fusion. Here, we analyze the role of each amino acid in E1E2 function, expressing 545 individual alanine mutants of E1E2 in human cells, incorporating them into infectious viral pseudoparticles, and testing them against 37 different monoclonal antibodies (MAbs) to ascertain full-length translation, folding, heterodimer assembly, CD81 binding, viral pseudoparticle incorporation, and infectivity. We propose a model describing the role of each critical residue in E1E2 functionality and use it to examine how MAbs neutralize infection by exploiting functionally critical sites of vulnerability on E1E2. Our results suggest that E1E2 is a surprisingly fragile protein complex where even a single alanine mutation at 92% of positions disrupts its function. The amino-acid-level targets identified are highly conserved and functionally critical and can be exploited for improved therapies and vaccines.
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Affiliation(s)
| | - Edgar Davidson
- Integral Molecular, Inc., 3711 Market St, Philadelphia, PA 19104, USA
| | | | - Mayda Hernandez
- Integral Molecular, Inc., 3711 Market St, Philadelphia, PA 19104, USA
| | - Erin Rosenberg
- Integral Molecular, Inc., 3711 Market St, Philadelphia, PA 19104, USA
| | - Ross Chambers
- Integral Molecular, Inc., 3711 Market St, Philadelphia, PA 19104, USA
| | - Matteo Castelli
- Laboratory of Medical Microbiology and Virology, University Vita-Salute San Raffaele, Milan, Italy
| | - Nicola Clementi
- Laboratory of Medical Microbiology and Virology, University Vita-Salute San Raffaele, Milan, Italy; IRCSS San Raffaele Hospital, Milan, Italy
| | - Nicasio Mancini
- Laboratory of Medical Microbiology and Virology, University Vita-Salute San Raffaele, Milan, Italy; IRCSS San Raffaele Hospital, Milan, Italy
| | - Justin R Bailey
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - James E Crowe
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Mansun Law
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Benjamin J Doranz
- Integral Molecular, Inc., 3711 Market St, Philadelphia, PA 19104, USA.
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43
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Kuo WT, Odenwald MA, Turner JR, Zuo L. Tight junction proteins occludin and ZO-1 as regulators of epithelial proliferation and survival. Ann N Y Acad Sci 2022; 1514:21-33. [PMID: 35580994 PMCID: PMC9427709 DOI: 10.1111/nyas.14798] [Citation(s) in RCA: 163] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Epithelial cells are the first line of mucosal defense. In the intestine, a single layer of epithelial cells must establish a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing the leakage of potentially harmful luminal materials. Key to this is the tight junction, which seals the paracellular space and prevents unrestricted leakage. The tight junction is a protein complex established by interactions between members of the claudin, zonula occludens, and tight junction-associated MARVEL protein (TAMP) families. Claudins form the characteristic tight junction strands seen by freeze-fracture microscopy and create paracellular channels, but the functions of ZO-1 and occludin, founding members of the zonula occludens and TAMP families, respectively, are less well defined. Recent studies have revealed that these proteins have essential noncanonical (nonbarrier) functions that allow them to regulate epithelial apoptosis and proliferation, facilitate viral entry, and organize specialized epithelial structures. Surprisingly, neither is required for intestinal barrier function or overall health in the absence of exogenous stressors. Here, we provide a brief overview of ZO-1 and occludin canonical (barrier-related) functions, and a more detailed examination of their noncanonical functions.
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Affiliation(s)
- Wei-Ting Kuo
- Graduate Institute of Oral Biology, National Taiwan University, Taipei, Taiwan.,Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | | | - Jerrold R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Li Zuo
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.,Anhui Medical University, Hefei, China
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44
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Proulx J, Ghaly M, Park IW, Borgmann K. HIV-1-Mediated Acceleration of Oncovirus-Related Non-AIDS-Defining Cancers. Biomedicines 2022; 10:biomedicines10040768. [PMID: 35453518 PMCID: PMC9024568 DOI: 10.3390/biomedicines10040768] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 03/22/2022] [Accepted: 03/22/2022] [Indexed: 11/25/2022] Open
Abstract
With the advent of combination antiretroviral therapy (cART), overall survival has been improved, and the incidence of acquired immunodeficiency syndrome (AIDS)-defining cancers has also been remarkably reduced. However, non-AIDS-defining cancers among human immunodeficiency virus-1 (HIV-1)-associated malignancies have increased significantly so that cancer is the leading cause of death in people living with HIV in certain highly developed countries, such as France. However, it is currently unknown how HIV-1 infection raises oncogenic virus-mediated cancer risks in the HIV-1 and oncogenic virus co-infected patients, and thus elucidation of the molecular mechanisms for how HIV-1 expedites the oncogenic viruses-triggered tumorigenesis in the co-infected hosts is imperative for developing therapeutics to cure or impede the carcinogenesis. Hence, this review is focused on HIV-1 and oncogenic virus co-infection-mediated molecular processes in the acceleration of non-AIDS-defining cancers.
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45
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Agnetti J, Desterke C, Gassama-Diagne A. Impact of HCV Infection on Hepatocyte Polarity and Plasticity. Pathogens 2022; 11:pathogens11030337. [PMID: 35335661 PMCID: PMC8955246 DOI: 10.3390/pathogens11030337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/23/2022] [Accepted: 03/07/2022] [Indexed: 02/01/2023] Open
Abstract
The hepatitis C virus (HCV) is an oncogenic virus that alters the cell polarization machinery in order to enter the hepatocyte and replicate. While these alterations are relatively well defined, their consequences in the evolution of the disease remain poorly documented. Since 2012, HCV infection can be effectively cured with the advent of direct acting antivirals (DAA). Nevertheless, patients cured of their HCV infection still have a high risk of developing hepatocellular carcinoma (HCC). Importantly, it has been shown that some of the deregulations induced by HCV are maintained despite a sustained virologic response (SVR), including the down-regulation of some hepatocyte functions such as bile acid metabolism, exemplifying cell dedifferentiation, and the up-regulation of the epithelial–mesenchymal transition (EMT). EMT is a process by which epithelial cells lose their differentiation and their specific polarity to acquire mesenchymal cell properties, including migration and extracellular matrix remodeling capabilities. Of note, epithelial cell polarity acts as a gatekeeper against EMT. Thus, it remains important to elucidate the mechanisms by which HCV alters polarity and promotes EMT that could participate in viral-induced hepatic carcinogenesis. In this review, we define the main steps involved in the polarization process of epithelial cells and recall the essential cellular actors involved. We also highlight the particularities of hepatocyte polarity, responsible for their unique morphology. We then focus on the alterations by HCV of epithelial cell polarity and the consequences of the transformation of hepatocytes involved in the carcinogenesis process.
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Affiliation(s)
- Jean Agnetti
- INSERM, UMR-S 1193, Université Paris-Sud, F-94800 Villejuif, France;
| | | | - Ama Gassama-Diagne
- INSERM, UMR-S 1193, Université Paris-Sud, F-94800 Villejuif, France;
- Correspondence:
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46
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Patten DA, Wilkinson AL, O'Keeffe A, Shetty S. Scavenger Receptors: Novel Roles in the Pathogenesis of Liver Inflammation and Cancer. Semin Liver Dis 2022; 42:61-76. [PMID: 34553345 PMCID: PMC8893982 DOI: 10.1055/s-0041-1733876] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The scavenger receptor superfamily represents a highly diverse collection of evolutionarily-conserved receptors which are known to play key roles in host homeostasis, the most prominent of which is the clearance of unwanted endogenous macromolecules, such as oxidized low-density lipoproteins, from the systemic circulation. Members of this family have also been well characterized in their binding and internalization of a vast range of exogenous antigens and, consequently, are generally considered to be pattern recognition receptors, thus contributing to innate immunity. Several studies have implicated scavenger receptors in the pathophysiology of several inflammatory diseases, such as Alzheimer's and atherosclerosis. Hepatic resident cellular populations express a diverse complement of scavenger receptors in keeping with the liver's homeostatic functions, but there is gathering interest in the contribution of these receptors to hepatic inflammation and its complications. Here, we review the expression of scavenger receptors in the liver, their functionality in liver homeostasis, and their role in inflammatory liver disease and cancer.
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Affiliation(s)
- Daniel A. Patten
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Alex L. Wilkinson
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Ayla O'Keeffe
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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47
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Abstract
In the 1970s, an unknown virus was suspected for documented cases of transfusion-associated hepatitis, a phenomenon called non-A, non-B hepatitis. In 1989, the infectious transmissible agent was identified and named hepatitis C virus (HCV) and, soon enough, the first diagnostic HCV antibody test was developed, which led to a dramatic decrease in new infections. Today, HCV infection remains a global health burden and a major cause of liver cirrhosis, hepatocellular carcinoma and liver transplantation. However, tremendous advances have been made over the decades, and HCV became the first curable, chronic viral infection. The introduction of direct antiviral agents revolutionized antiviral treatment, leading to viral eradication in more than 98% of all patients infected with HCV. This Perspective discusses the history of HCV research, which reads like a role model for successful translational research: starting from a clinical observation, specific therapeutic agents were developed, which finally were implemented in national and global elimination programmes.
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Affiliation(s)
- Michael P. Manns
- grid.10423.340000 0000 9529 9877Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- grid.10423.340000 0000 9529 9877Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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48
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Hu Y, Xie X, Yang L, Wang A. A Comprehensive View on the Host Factors and Viral Proteins Associated With Porcine Epidemic Diarrhea Virus Infection. Front Microbiol 2021; 12:762358. [PMID: 34950116 PMCID: PMC8688245 DOI: 10.3389/fmicb.2021.762358] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 10/26/2021] [Indexed: 11/17/2022] Open
Abstract
Porcine epidemic diarrhea virus (PEDV), a coronavirus pathogen of the pig intestinal tract, can cause fatal watery diarrhea in piglets, thereby causing huge economic losses to swine industries around the world. The pathogenesis of PEDV has intensively been studied; however, the viral proteins of PEDV and the host factors in target cells, as well as their interactions, which are the foundation of the molecular mechanisms of viral infection, remain to be summarized and updated. PEDV has multiple important structural and functional proteins, which play various roles in the process of virus infection. Among them, the S and N proteins play vital roles in biological processes related to PEDV survival via interacting with the host cell proteins. Meanwhile, a number of host factors including receptors are required for the infection of PEDV via interacting with the viral proteins, thereby affecting the reproduction of PEDV and contributing to its life cycle. In this review, we provide an updated understanding of viral proteins and host factors, as well as their interactions in terms of PEDV infection. Additionally, the effects of cellular factors, events, and signaling pathways on PEDV infection are also discussed. Thus, these comprehensive and profound insights should facilitate for the further investigations, control, and prevention of PEDV infection.
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Affiliation(s)
- Yi Hu
- Laboratory of Animal Disease Prevention and Control and Animal Model, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, College of Veterinary Medicine, Hunan Agricultural University, Changsha, China
| | - Xiaohong Xie
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha, China
| | - Lingchen Yang
- Laboratory of Animal Disease Prevention and Control and Animal Model, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, College of Veterinary Medicine, Hunan Agricultural University, Changsha, China
| | - Aibing Wang
- Laboratory of Animal Disease Prevention and Control and Animal Model, Hunan Provincial Key Laboratory of Protein Engineering in Animal Vaccines, College of Veterinary Medicine, Hunan Agricultural University, Changsha, China.,PCB Biotechnology, LLC, Rockville, MD, United States
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49
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Aldana-Bitar J, Moore J, Budoff MJ. LDL receptor and pathogen processes: Functions beyond normal lipids. J Clin Lipidol 2021; 15:773-781. [PMID: 34645587 DOI: 10.1016/j.jacl.2021.09.048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 10/20/2022]
Abstract
Although the role of the LDL receptor concerning lipids is well known, its role in various viral and parasitic infections, and in regulating the inflammatory response is poorly understood. Several infectious agents use the LDL receptor as a port of entry, and others depend on it for their cycle of infection. In this review, we focus on the discovery, structure, and normal function of the LDL receptor, as well as its role in a selection of infections. The LDL receptor plays an important role in certain infections and is a potential target for treatment deserving further research.
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Affiliation(s)
- Jairo Aldana-Bitar
- Division of Cardiology, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
| | - Jeff Moore
- Division of Cardiology, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA
| | - Matthew J Budoff
- Division of Cardiology, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502, USA.
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50
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Abstract
Viral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets.
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Affiliation(s)
- Han-Yuan Liu
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
- Current affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Palo Alto, California 94305, USA;
| | - Priscilla L Yang
- Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
- Current affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Palo Alto, California 94305, USA;
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