Friday, April 4, 2025
4/4/2025
The vital role of T403 phosphorylation of STAT2 in post-viral bacterial pneumonia - Project Summary Post-viral bacterial pneumonia is a leading cause of death in pandemics. Since we use different strategies to fight viruses and bacteria, host innate immune responses are confused and impaired when both types of infection occur simultaneously, resulting in higher mortality in post-viral bacterial pneumonia. Determining the key events in the initial viral infection that disturb the subsequent antibacterial responses will guide therapies in treating post-viral bacterial pneumonia. STAT2, as a critical component of IFN-I signaling, is essential for the antiviral response, but elicits detrimental effects in antibacterial response though yet-unknown mechanisms. We discovered a novel T403 phosphorylation of STAT2, stimulated by virus infections, enabling an efficient antiviral response in infected cells. This project sheds new light on the role of STAT2 T403 phosphorylation in the pathogenesis of post-viral bacterial pneumonia from two perspectives: (1) the action of IFN: IFN-I is essential to limit viral dissemination, but with enigmatic functions in the subsequent bacterial infection. As the critical component in IFN-I signaling, STAT2 suppresses bacterial clearance during IAV-bacterial co-infection. Our recent discovery provides structural insight into how T403 phosphorylation, induced by prior viral infection, primes IFN-I signaling in macrophages and neutrophils, which may explain IFN-associated increased susceptibility to bacterial infection. (2) the regulation of inflammation: Viral infection increases progression of secondary bacterial sepsis 6-fold. We discovered that STAT2 T403 phosphorylation promotes NF-κB-driven inflammatory response in macrophages. In agreement with this finding, our preliminary data show that blocking STAT2 T403 phosphorylation protects mice from bacterially-induced sepsis. These findings suggest T403 phosphorylation plays a critical role in promoting proinflammatory phenotype of macrophages thereby exacerbating inflammation-associated lung injury. In conclusion, we hypothesize that T403 phosphorylation of STAT2 is a post-viral infection event that impairs bacterial clearance and exacerbates the severity of inflammation-associated lung injury in subsequent bacterial pneumonia. This project will carry our understanding from structural and mechanistic analyses forward to phenotypic changes in vitro and in vivo. We will determine the kinetics of virus-induced T403 phosphorylation in mice and investigate its correlation with lung injury prognosis in ARDS patients. Since macrophages and neutrophils are the key responders to bacterial infection, we will focus on determining the impact of T403 phosphorylation on their functions in bacterially induced lung injury. Finally, we will determine how T403 phosphorylation contributes to the development of post-IAV bacterial pneumonia and evaluate the ability of a clinical TBK1/IKK-i inhibitor that blocks STAT2 T403 phosphorylation to ameliorate lung injury in our model. Completion of this project will allow us to comprehensively analyze this new regulatory mechanism in bacterially induced lung injury, and potentially to develop T403 phosphorylation as a critical biomarker and potential therapeutic target in post-viral bacterial pneumonia.
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