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LY6E impairs coronavirus fusion and confers immune control of viral disease

Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, Markus Hoffmann, H. Heinrich Hoffmann, Mohsan Saeed, Ronald Dijkman, Eike Steinmann, Mary Wight-Carter, Natasha W. Hanners, Stefan Pöhlmann, Tom Gallagher, Daniel Todt, Gert Zimmer, Charles M. Rice, View ORCID ProfileJohn W. Schoggins, Volker Thiel
doi: https://doi.org/10.1101/2020.03.05.979260
Stephanie Pfaender
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
3Department for Molecular & Medical Virology, Ruhr-Universität Bochum, Germany
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Katrina B. Mar
4Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Eleftherios Michailidis
5Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
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Annika Kratzel
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Dagny Hirt
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Philip V’kovski
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Wenchun Fan
4Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Nadine Ebert
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Hanspeter Stalder
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Hannah Kleine-Weber
6Deutsches Primatenzentrum GmbH, Leibniz-Institut für Primatenforschung, Göttingen, Germany
7Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany
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Markus Hoffmann
6Deutsches Primatenzentrum GmbH, Leibniz-Institut für Primatenforschung, Göttingen, Germany
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H. Heinrich Hoffmann
5Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
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Mohsan Saeed
5Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
8Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA; National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, USA
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Ronald Dijkman
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Eike Steinmann
3Department for Molecular & Medical Virology, Ruhr-Universität Bochum, Germany
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Mary Wight-Carter
9Animal Resource Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Natasha W. Hanners
10Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Stefan Pöhlmann
6Deutsches Primatenzentrum GmbH, Leibniz-Institut für Primatenforschung, Göttingen, Germany
7Faculty of Biology and Psychology, University Göttingen, Göttingen, Germany
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Tom Gallagher
11Department of Microbiology and Immunology, Loyola University Chicago, Chicago, USA
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Daniel Todt
3Department for Molecular & Medical Virology, Ruhr-Universität Bochum, Germany
12European Virus Bioinformatics Center (EVBC), Jena, Germany
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Gert Zimmer
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Charles M. Rice
5Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
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  • For correspondence: volker.thiel@vetsuisse.unibe.ch john.schoggins@utsouthwestern.edu ricec@rockefeller.edu
John W. Schoggins
4Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • ORCID record for John W. Schoggins
  • For correspondence: volker.thiel@vetsuisse.unibe.ch john.schoggins@utsouthwestern.edu ricec@rockefeller.edu
Volker Thiel
1Institute of Virology and Immunology, Bern and Mittelhäusern, Switzerland
2Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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  • For correspondence: volker.thiel@vetsuisse.unibe.ch john.schoggins@utsouthwestern.edu ricec@rockefeller.edu
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ABSTRACT

Zoonotic coronaviruses (CoVs) are significant threats to global health, as exemplified by the recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. Host immune responses to CoV are complex and regulated in part through antiviral interferons. However, the interferon-stimulated gene products that inhibit CoV are not well characterized2. Here, we show that interferon-inducible lymphocyte antigen 6 complex, locus E (LY6E) potently restricts cellular infection by multiple CoVs, including SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV). Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in hematopoietic cells were highly susceptible to murine CoV infection. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic and splenic immune cells and reduction in global antiviral gene pathways. Accordingly, we found that Ly6e directly protects primary B cells and dendritic cells from murine CoV infection. Our results demonstrate that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo, knowledge that could help inform strategies to combat infection by emerging CoV.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 07, 2020.
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LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, Markus Hoffmann, H. Heinrich Hoffmann, Mohsan Saeed, Ronald Dijkman, Eike Steinmann, Mary Wight-Carter, Natasha W. Hanners, Stefan Pöhlmann, Tom Gallagher, Daniel Todt, Gert Zimmer, Charles M. Rice, John W. Schoggins, Volker Thiel
bioRxiv 2020.03.05.979260; doi: https://doi.org/10.1101/2020.03.05.979260
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LY6E impairs coronavirus fusion and confers immune control of viral disease
Stephanie Pfaender, Katrina B. Mar, Eleftherios Michailidis, Annika Kratzel, Dagny Hirt, Philip V’kovski, Wenchun Fan, Nadine Ebert, Hanspeter Stalder, Hannah Kleine-Weber, Markus Hoffmann, H. Heinrich Hoffmann, Mohsan Saeed, Ronald Dijkman, Eike Steinmann, Mary Wight-Carter, Natasha W. Hanners, Stefan Pöhlmann, Tom Gallagher, Daniel Todt, Gert Zimmer, Charles M. Rice, John W. Schoggins, Volker Thiel
bioRxiv 2020.03.05.979260; doi: https://doi.org/10.1101/2020.03.05.979260

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