SARS-CoV-2 Spike evolution influences GBP and IFITM sensitivity

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Abstract

SARS-CoV-2 spike requires proteolytic processing for viral entry. The presence of a polybasic furin-cleavage site (FCS) in spike, and evolution towards an optimised FCS by dominant variants of concern (VOCs), are linked to enhanced infectivity and transmission. Here we show that interferon-inducible antiviral restriction factors Guanylate binding proteins (GBP) 2 and 5 interfere with furin-mediated cleavage of SARS-CoV-2 spike and inhibit the infectivity of early-lineage Wuhan-Hu-1, while VOCs Alpha and Delta have evolved to escape restriction. Strikingly, we find Omicron is unique amongst VOCs, being restricted by GBP2/5, and also IFITM1, 2 and 3. Replacing the spike S2 domain in Omicron with Delta shows S2 is the determinant of entry route and IFITM sensitivity. We conclude that VOC evolution under different selective pressures has influenced sensitivity to spike-targeting restriction factors, with Omicron selecting spike changes that not only mediate antibody escape, and altered tropism, but also sensitivity to innate immunity.

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  1. SciScore for 10.1101/2022.03.07.481785: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Twenty micrograms of cell lysate and an equal volume of purified virus were separated by SDS-PAGE, transferred to nitrocellulose membrane and membranes probed using the following primary antibodies: anti-SARS-CoV Spike (100% overlap with the SARS-CoV-2 epitope) (Invitrogen, PA1-41165, 1:1000)
    anti-SARS-CoV
    suggested: None
    SARS-CoV-2 epitope
    suggested: None
    PA1-41165
    suggested: (Thermo Fisher Scientific Cat# PA1-41165, RRID:AB_1087210)
    , anti SARS-CoV nucleoprotein (N) monoclonal antibody …