Inhibition of SARS-CoV-2 Infection by Human Defensin HNP1 and Retrocyclin RC-101 |
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| Affiliation: | 1. Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA;2. Infectious Diseases Institute, The Ohio State University, Columbus, OH 43210, USA;3. Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210, USA;4. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA;5. Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Science, and Shanghai Institute of Infectious Disease and Biosecurity, School of Public Health, Fudan University, Shanghai 200032, China;1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA;2. Department of Immunology, University of Washington, Seattle, WA 98109, USA;3. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA;1. Clinic for Gastroenterology, Hepatology, and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany;2. Laboratório de Virologia, Departamento de Microbiologia, Imunologia e Parasitologia, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil;3. Max von Pettenkofer Institute & Gene Center, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU München, Munich, Germany;4. InBIO – Research Network in Biodiversity and Evolutionary Biology, CIBIO, Campus de Vairão, Universidade do Porto, Vairão, Portugal;5. Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal;6. Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA |
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| Abstract: | Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is an enveloped virus responsible for the COVID-19 pandemic. The emergence of new potentially more transmissible and vaccine-resistant variants of SARS-CoV-2 is an ever-present threat. Thus, it remains essential to better understand innate immune mechanisms that can inhibit the virus. One component of the innate immune system with broad antipathogen, including antiviral, activity is a group of cationic immune peptides termed defensins. The ability of defensins to neutralize enveloped and non-enveloped viruses and to inactivate numerous bacterial toxins correlate with their ability to promote the unfolding of proteins with high conformational plasticity. We found that human neutrophil α-defensin HNP1 binds to SARS-CoV-2 Spike protein with submicromolar affinity that is more than 20 fold stronger than its binding to serum albumin. As such, HNP1, as well as a θ-defensin retrocyclin RC-101, both interfere with Spike-mediated membrane fusion, Spike-pseudotyped lentivirus infection, and authentic SARS-CoV-2 infection in cell culture. These effects correlate with the abilities of the defensins to destabilize and precipitate Spike protein and inhibit the interaction of Spike with the ACE2 receptor. Serum reduces the anti-SARS-CoV-2 activity of HNP1, though at high concentrations, HNP1 was able to inactivate the virus even in the presence of serum. Overall, our results suggest that defensins can negatively affect the native conformation of SARS-CoV-2 Spike, and that α- and θ-defensins may be valuable tools in developing SARS-CoV-2 infection prevention strategies. |
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| Keywords: | SARS-CoV-2 innate immunity defensins human neutrophil peptide HNP1 retrocyclin RC-101 |
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