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Myeloid TBK1 Signaling Contributes to the Immune Response to Influenza.

ABSTRACT: Macrophages provide key elements of the host response to influenza A virus (IAV) infection, including expression of type I IFN and inflammatory cytokines and chemokines. TBK1 (TNF receptor-associated factor family member-associated NF-κB activator-binding kinase 1) contributes to IFN expression and antiviral 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 BAL fluid relative to wild-type mice despite no differences in viral load. Mice lacking myeloid TBK1 showed less recruitment of CD64⁺SiglecF^-Ly6C^hi inflammatory macrophages, less expression of inflammatory cytokines in the BAL fluid, and less expression of both IFN regulatory factor and NF-κB target genes in the lung. Analysis of sorted alveolar macrophages, inflammatory macrophages, and lung interstitial macrophages 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.

SUBMITTER: Hagan RS

PROVIDER: S-EPMC6397979 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-?) induced by Sendai virus and poly(I·C), while knockdown of Cdc25A enhances the transcription of IFN-? stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-?. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1-transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-? reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-?. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity.IMPORTANCE The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-? transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-?. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

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Myeloid TBK1 Signaling Contributes to the Immune Response to Influenza.

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