# The vital role of T403 phosphorylation of STAT2 in post-viral bacterial pneumonia

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $563,500

## Abstract

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....

## Key facts

- **NIH application ID:** 10879891
- **Project number:** 1R01HL166544-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** YUXIN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,500
- **Award type:** 1
- **Project period:** 2024-03-20 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879891

## Citation

> US National Institutes of Health, RePORTER application 10879891, The vital role of T403 phosphorylation of STAT2 in post-viral bacterial pneumonia (1R01HL166544-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879891. Licensed CC0.

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