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Proc Natl Acad Sci U S A Membrane-tethered Mucin-Like Polypeptides Sterically Inhibit Binding and Slow Fusion Kinetics of Influenza A Virus

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  • Proc Natl Acad Sci U S A Membrane-tethered Mucin-Like Polypeptides Sterically Inhibit Binding and Slow Fusion Kinetics of Influenza A Virus


    Proc Natl Acad Sci U S A


    . 2020 May 26;201921962.
    doi: 10.1073/pnas.1921962117. Online ahead of print.
    Membrane-tethered Mucin-Like Polypeptides Sterically Inhibit Binding and Slow Fusion Kinetics of Influenza A Virus


    Corleone S Delaveris 1 , Elizabeth R Webster 1 , Steven M Banik 1 , Steven G Boxer 2 , Carolyn R Bertozzi 2 3



    Affiliations

    Abstract

    The mechanism(s) by which cell-tethered mucins modulate infection by influenza A viruses (IAVs) remain an open question. Mucins form both a protective barrier that can block virus binding and recruit IAVs to bind cells via the sialic acids of cell-tethered mucins. To elucidate the molecular role of mucins in flu pathogenesis, we constructed a synthetic glycocalyx to investigate membrane-tethered mucins in the context of IAV binding and fusion. We designed and synthesized lipid-tethered glycopolypeptide mimics of mucins and added them to lipid bilayers, allowing chemical control of length, glycosylation, and surface density of a model glycocalyx. We observed that the mucin mimics undergo a conformational change at high surface densities from a compact to an extended architecture. At high surface densities, asialo mucin mimics inhibited IAV binding to underlying glycolipid receptors, and this density correlated to the mucin mimic's conformational transition. Using a single virus fusion assay, we observed that while fusion of virions bound to vesicles coated with sialylated mucin mimics was possible, the kinetics of fusion was slowed in a mucin density-dependent manner. These data provide a molecular model for a protective mechanism by mucins in IAV infection, and therefore this synthetic glycocalyx provides a useful reductionist model for studying the complex interface of host-pathogen interactions.

    Keywords: glycobiology; influenza A virus; mucin.

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