Hagan RS, Torres-Castillo J, Doerschuk CM. Myeloid TBK1 Signaling Contributes to the Immune Response to Influenza. Am J Respir Cell Mol Biol. 2018 Oct 5.
Macrophages provide key elements of the host response to influenza A virus (IAV) infection, including expression of type I interferon (IFN) and inflammatory cytokines and chemokines. TANK-binding kinase 1 (TBK1) contributes to IFN expression and anti-viral responses in some cell types, but its role in the innate response to IAV in vivo is unknown. We hypothesized that macrophage TBK1 contributes to both IFN and non-IFN components of host defense and IAV pathology. We generated myeloid-conditional TBK1 knockout mice and assessed the in vitro and in vivo consequences of IAV infection. Myeloid-specific loss of TBK1 in vivo resulted in less severe host response to IAV, as assessed by decreased mortality, weight loss, and hypoxia and less inflammatory changes in BALF relative to wildtype (WT) mice despite no differences in viral load. Mice lacking myeloid TBK1 showed less recruitment of CD64+SiglecF-Ly6Chi inflammatory macrophages (InfMs), less expression of inflammatory cytokines in the BALF, and less expression of both interferon regulatory factor (IRF) and NF-κB target genes in the lung. Analysis of sorted AMs, InfMs, and lung interstitial macrophages (IMs) revealed that each subpopulation requires TBK1 for distinct components of the response to IAV infection. Our findings define roles for myeloid TBK1 in IAV-induced lung inflammation apart from IFN type I expression and point to myeloid TBK1 as a central and cell type-specific regulator of virus-induced lung damage.
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