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    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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