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    The polybasic cleavage site in the SARS-CoV-2 spike PROTEIN modulates viral sensitivity to Type I IFN and IFITM2


    doi:10.1101/2020.12.19.423592 Date: 2020-12-20 Source: bioRxiv

    The cellular entry of severe acute respiratory syndrome MESHD-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein PROTEIN (S). The presence of a polybasic cleavage site in SARS-CoV-2 S at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the S precursor by furin HGNC-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons, and more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2 HGNC and the degree of this restriction is governed by route of viral entry. Removal of the cleavage site in the spike protein PROTEIN renders SARS-CoV-2 entry highly pH- and cathepsin-dependent in late endosomes where, like SARS-CoV-1 S MESHD, it is more sensitive to IFITM2 HGNC restriction. Furthermore, we find that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 HGNC expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests therapeutic strategies that target furin HGNC-mediated cleavage of SARS-CoV-2 S MESHD may reduce viral replication through the activity of type I IFNs. IMPORTANCEThe furin HGNC cleavage site in the S protein PROTEIN is a distinguishing feature of SARS-CoV-2 and has been proposed to be a determinant for the higher transmissibility between individuals compared to SARS-CoV-1. One explanation for this is that it permits more efficient activation of fusion at or near the cell surface rather than requiring processing in the endosome of the target cell. Here we show that SARS-CoV-2 is inhibited by antiviral membrane protein IFITM2 HGNC, and that the sensitivity is exacerbated by deletion of the furin HGNC cleavage site which restricts viral entry to low pH compartments. Furthermore, we find that IFITM2 HGNC is a significant effector of the antiviral activity of type I interferons against SARS-CoV-2 replication. We suggest one role of the furin HGNC cleavage site is to reduce SARS-CoV-2 sensitivity to innate immune restriction, and thus may represent a potential therapeutic target for COVID-19 MESHD treatment development.

    IFITM proteins promote SARS-CoV-2 infection MESHD in human lung cells

    Authors: Caterina Prelli Bozzo; Rayhane Nchioua; Meta Volcic; Lukas Wettstein; Tatjana Weil; Jana Krueger; Sandra Heller; Carina Conzelmann; Janis A Mueller; Ruediger Gross; Fabian Zech; Desiree Schuetz; Lennart Koepke; Christina Martina Stuerzel; Christiane Schueler; Saskia Stenzel; Elisabeth Braun; Johanna Weiss; Daniel Sauter; Jan Muench; Steffen Stenger; Kei Sato; Alexander Kleger; Christine Goffinet; Konstantin Maria Johannes Sparrer; Frank Kirchhoff; Austin D. Swafford; Karsten Zengler; Susan Cheng; Michael Inouye; Teemu Niiranen; Mohit Jain; Veikko Salomaa; Jeffrey D. Esko; Nathan E Lewis; Rob Knight

    doi:10.1101/2020.08.18.255935 Date: 2020-08-18 Source: bioRxiv

    Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) restrict numerous viral pathogens and are thought to prevent infection by severe acute respiratory syndrome coronaviruses (SARS-CoVs MESHD). However, most evidence comes from single-round pseudoparticle infection of cells artificially overexpressing IFITMs. Here, we confirmed that overexpression of IFITMs blocks pseudoparticle infections mediated by the Spike proteins PROTEIN of {beta}-coronaviruses including pandemic SARS-CoV-2. In striking contrast, however, endogenous IFITM expression promoted genuine SARS-CoV-2 infection MESHD in human lung cells both in the presence and absence of interferon. IFITM2 HGNC was most critical for efficient entry of SARS-CoV-2 and enhanced virus production from Calu-3 cells by several orders of magnitude. IFITMs are expressed and further induced by interferons in the lung representing the primary site of SARS-CoV-2 infection MESHD as well as in other relevant tissues. Our finding that IFITMs enhance SARS-CoV-2 infection MESHD under conditions approximating the in vivo situation shows that they may promote viral invasion during COVID-19 MESHD. HIGHLIGHTSO_LIOverexpression of IFITM1, 2 and 3 restricts SARS-CoV-2 infection MESHD C_LIO_LIEndogenous IFITM1, 2 and 3 boost SARS-CoV-2 infection MESHD of human lung cells C_LIO_LIIFITM2 is critical for efficient entry of SARS-CoV-2 in Calu-3 cells C_LI

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

    Authors: Guoli Shi; Adam D Kenney; Elena Kudryashova; Lizhi Zhang; Luanne Hall-Stoodley; Richard Robinson; Dmitri Kudryashov; Alex A. S Compton; Jacob S Yount

    doi:10.1101/2020.08.11.246678 Date: 2020-08-11 Source: bioRxiv

    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 PROTEIN-pseudotyped virus and genuine SARS-CoV-2 infections MESHD SARS-CoV-2 infections MESHD are generally restricted by expression of human IFITM1 HGNC, IFITM2 HGNC, and IFITM3 HGNC, using both gain- and loss-of-function approaches. Mechanistically, restriction of SARS-CoV-2 occurred independently of IFITM3 HGNC S-palmitoylation sites, indicating a restrictive capacity that is distinct from reported inhibition of other viruses. In contrast, the IFITM3 HGNC amphipathic helix and its amphipathic properties were required for virus restriction. Mutation of residues within the human IFITM3 HGNC endocytosis-promoting Yxx{Phi} motif converted human IFITM3 HGNC into an enhancer of SARS-CoV-2 infection MESHD, and cell-to-cell fusion assays confirmed the ability of endocytic mutants to enhance Spike-mediated fusion with the plasma membrane. Overexpression of TMPRSS2 HGNC, which reportedly increases plasma membrane fusion versus endosome fusion of SARS-CoV-2, attenuated IFITM3 HGNC restriction and converted amphipathic helix mutants into strong enhancers of infection. In sum, these data uncover new pro- and anti-viral mechanisms of IFITM3 HGNC, 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 HGNC on SARS-CoV-2 infections MESHD 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.

    Syncytia formation by SARS-CoV-2 infected cells

    Authors: Julian Buchrieser; Jeremy Dufloo; Mathieu Hubert; Blandine Monel; Delphine Planas; Maaran Michael Rajah; Cyril Planchais; Francoise Porrot; Florence Guivel-Benhassine; Sylvie van der Werf; Nicoletta Casartelli; Hugo Mouquet; Timothee Bruel; Olivier Schwartz

    doi:10.1101/2020.07.14.202028 Date: 2020-07-14 Source: bioRxiv

    Severe cases of COVID-19 MESHD are associated with extensive lung damage MESHD and the presence of infected multinucleated syncytial pneumocytes. The viral and cellular mechanisms regulating the formation of these syncytia are not well understood. Here, we show that SARS-CoV-2 infected MESHD cells express the viral Spike protein (S PROTEIN) at their surface and fuse with ACE2 HGNC-positive neighbouring cells. Expression of S without any other viral proteins triggers syncytia formation. Type-I interferon (IFN)-induced transmembrane proteins (IFITMs), a family of restriction factors that block the entry of many viruses, inhibit S-mediated fusion, with IFITM1 HGNC being more active than IFITM2 HGNC and IFITM3 HGNC. On the contrary, the TMPRSS2 serine protease, which is known to enhance infectivity of cell-free virions, processes both S and ACE2 HGNC and increases syncytia MESHD formation by accelerating the fusion process. TMPRSS2 HGNC thwarts the antiviral effect of IFITMs. Our results show that the pathological effects of SARS-CoV-2 are modulated by cellular proteins that either inhibit or facilitate syncytia formation. One Sentence SummarySyncytia produced by SARS-CoV-2 infected cells and regulation of their formation by IFITMs and TMPRSS2 HGNC.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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