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Opposing activities of IFITM proteins in SARS-CoV-2 infection

Guoli Shi, Adam D. Kenney, Elena Kudryashova, Lizhi Zhang, Luanne Hall-Stoodley, Richard T. Robinson, Dmitri S. Kudryashov, Alex A. Compton, Jacob S. Yount
doi: https://doi.org/10.1101/2020.08.11.246678
Guoli Shi
1HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD, USA
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Adam D. Kenney
2Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
3Viruses and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
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Elena Kudryashova
3Viruses and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
4Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA
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Lizhi Zhang
2Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
3Viruses and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
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Luanne Hall-Stoodley
2Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
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Richard T. Robinson
2Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
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Dmitri S. Kudryashov
3Viruses and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
4Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA
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Alex A. Compton
1HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD, USA
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  • For correspondence: Alex.Compton@nih.gov Jacob.Yount@osumc.edu
Jacob S. Yount
2Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH, USA
3Viruses and Emerging Pathogens Program, Infectious Diseases Institute, The Ohio State University, Columbus, OH, USA
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  • For correspondence: Alex.Compton@nih.gov Jacob.Yount@osumc.edu
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Abstract

Interferon-induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. Here we show that SARS-CoV-2 Spike-pseudotyped virus and genuine SARS-CoV-2 infections are generally restricted by expression of human IFITM1, IFITM2, and IFITM3, using both gain- and loss-of-function approaches. Mechanistically, restriction of SARS-CoV-2 occurred independently of IFITM3 S-palmitoylation sites, indicating a restrictive capacity that is distinct from reported inhibition of other viruses. In contrast, the IFITM3 amphipathic helix and its amphipathic properties were required for virus restriction. Mutation of residues within the human IFITM3 endocytosis-promoting YxxΦ motif converted human IFITM3 into an enhancer of SARS-CoV-2 infection, and cell-to-cell fusion assays confirmed the ability of endocytic mutants to enhance Spike-mediated fusion with the plasma membrane. Overexpression of TMPRSS2, which reportedly increases plasma membrane fusion versus endosome fusion of SARS-CoV-2, attenuated IFITM3 restriction and converted amphipathic helix mutants into strong enhancers of infection. In sum, these data uncover new pro- and anti-viral mechanisms of IFITM3, with clear distinctions drawn between enhancement of viral infection at the plasma membrane and amphipathicity-based mechanisms used for endosomal virus restriction. Indeed, the net effect of IFITM3 on SARS-CoV-2 infections may be a result of these opposing activities, suggesting that shifts in the balance of these activities could be coopted by viruses to escape this important first line innate defense mechanism.

Competing Interest Statement

The authors have declared no competing interest.

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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 August 11, 2020.
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Opposing activities of IFITM proteins in SARS-CoV-2 infection
Guoli Shi, Adam D. Kenney, Elena Kudryashova, Lizhi Zhang, Luanne Hall-Stoodley, Richard T. Robinson, Dmitri S. Kudryashov, Alex A. Compton, Jacob S. Yount
bioRxiv 2020.08.11.246678; doi: https://doi.org/10.1101/2020.08.11.246678
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Opposing activities of IFITM proteins in SARS-CoV-2 infection
Guoli Shi, Adam D. Kenney, Elena Kudryashova, Lizhi Zhang, Luanne Hall-Stoodley, Richard T. Robinson, Dmitri S. Kudryashov, Alex A. Compton, Jacob S. Yount
bioRxiv 2020.08.11.246678; doi: https://doi.org/10.1101/2020.08.11.246678

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