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.
Highlights
Human influenza viruses, such as seasonal influenza viruses and pandemic 2009 A(H1N1) virus (H1N1 hereinafter), usually lead to upper respiratory infection with mild-to-moderate symptoms (To et al, 2013), albeit occasionally causing life-threatening pneumonia in patients with chronic underlying diseases, or even in healthy individuals
Glycine decarboxylase (GLDC) was prioritized as a susceptibility gene to H7N9 infection and severe H1N1 infection by integrating genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) analysis
The differential expression levels of GLDC are significantly correlated to rs1755609 genotypes in lymphoblast cell lines (LCLs) and human lung tissues, the risk variants corresponding to higher GLDC expression
Summary
Human influenza viruses, such as seasonal influenza viruses and pandemic 2009 A(H1N1) virus (H1N1 hereinafter), usually lead to upper respiratory infection with mild-to-moderate symptoms (To et al, 2013), albeit occasionally causing life-threatening pneumonia in patients with chronic underlying diseases, or even in healthy individuals. The variable susceptibility to H7N9 infection and diversified disease severity in pandemic H1N1 infection prompted us to decipher the genetic susceptibility and identify host gene predisposing to severe influenza, i.e., H7N9 and severe H1N1 infection. To identify host susceptibility gene to severe influenza, we previously conducted genome-wide association studies (GWAS) in two study cohorts: the H7N9 cohort including H7N9 patients versus healthy controls who were heavily exposed to the virus (Chen et al, 2015), and the H1N1 cohort consisting of severe H1N1 patients versus control patients with mild H1N1 infection (Zhou et al, 2012). Glycine decarboxylase (GLDC) emerged as a potential susceptibility gene in both study cohorts
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