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Identification and characterization of GLDC as host susceptibility gene to severe influenza

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  • Identification and characterization of GLDC as host susceptibility gene to severe influenza

    EMBO Mol Med. 2018 Nov 28. pii: e9528. doi: 10.15252/emmm.201809528. [Epub ahead of print]
    Identification and characterization of GLDC as host susceptibility gene to severe influenza.

    Zhou J1,2,3, Wang D2, Wong BH2, Li C2, Poon VK2, Wen L2, Zhao X2, Chiu MC2, Liu X2, Ye Z2, Yuan S2, Sze KH2, Chan JF1,2,3,4,5,6, Chu H1,2,3, To KK1,2,3,4,5,6, Yuen KY7,2,3,4,5,6.
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    Abstract

    Glycine decarboxylase (GLDC) was prioritized as a candidate susceptibility gene to severe influenza in humans. The higher expression of GLDC derived from genetic variations may confer a higher risk to H7N9 and severe H1N1 infection. We sought to characterize GLDC as functional susceptibility gene that GLDC may intrinsically regulate antiviral response, thereby impacting viral replication and disease outcome. We demonstrated that GLDC inhibitor AOAA and siRNA depletion boosted IFNβ- and IFN-stimulated genes (ISGs) in combination with PolyI:C stimulation. GLDC inhibition and depletion significantly amplified antiviral response of type I IFNs and ISGs upon viral infection and suppressed the replication of H1N1 and H7N9 viruses. Consistently, GLDC overexpression significantly promoted viral replication due to the attenuated antiviral responses. Moreover, GLDC inhibition in H1N1-infected BALB/c mice recapitulated the amplified antiviral response and suppressed viral growth. AOAA provided potent protection to the infected mice from lethal infection, comparable to a standard antiviral against influenza viruses. Collectively, GLDC regulates cellular antiviral response and orchestrates viral growth. GLDC is a functional susceptibility gene to severe influenza in humans.


    KEYWORDS:

    GLDC ; antiviral response; genetic susceptibility; severe influenza; viral replication

    PMID: 30498026 DOI: 10.15252/emmm.201809528
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