TBK1 Is Required for Host Defense Functions Distinct from Type I IFN Expression and Myeloid Cell Recruitment in Murine Streptococcus pneumoniae Pneumonia

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Abstract
Bacterial pneumonia induces the rapid recruitment and activation of neutrophils and macrophages into the lung, and these cells contribute to bacterial clearance and other defense functions. TBK1 (TANK-binding kinase 1) performs many functions, including activation of the type I IFN pathway and regulation of autophagy and mitophagy, but its contribution to antibacterial defenses in the lung is unclear. We previously showed that lung neutrophils upregulate mRNAs for TBK1 and its accessory proteins during Streptococcus pneumoniae pneumonia, despite low or absent expression of type I IFN in these cells. We hypothesized that TBK1 performs key antibacterial functions in pneumonia apart from type I IFN expression. Using TBK1 null mice, we show that TBK1 contributes to antibacterial defenses and promotes bacterial clearance and survival. TBK1 null mice express lower concentrations of many cytokines in the infected lung. Conditional deletion of TBK1 with LysMCre results in TBK1 deletion from macrophages but not neutrophils. LysMCre TBK1 mice have no defect in cytokine expression, implicating a nonmacrophage cell type as a key TBK1-dependent cell. TBK1 null neutrophils have no defect in recruitment to the infected lung but show impaired activation of p65/NF-κB and STAT1 and lower expression of reactive oxygen species, IFNγ, and IL12p40. TLR1/2 and 4 agonists each induce phosphorylation of TBK1 in neutrophils. Surprisingly, neutrophil TBK1 activation in vivo does not require the adaptor STING. Thus, TBK1 is a critical component of STING-independent antibacterial responses in the lung, and TBK1 is necessary for multiple neutrophil functions.
Funding Information
  • National Heart, Lung, and Blood Institute (1K08HL143271)
  • National Heart, Lung, and Blood Institute (5K12HL119998)
  • National Heart, Lung, and Blood Institute (R01HL114388)
  • National Heart, Lung, and Blood Institute (R01HL145396)
  • National Heart, Lung, and Blood Institute (R03HL155249)
  • National Heart, Lung, and Blood Institute (1K08HL143271)
  • National Heart, Lung, and Blood Institute (5K12HL119998)
  • National Heart, Lung, and Blood Institute (R01HL114388)
  • National Heart, Lung, and Blood Institute (R01HL145396)
  • National Heart, Lung, and Blood Institute (R03HL155249)

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