# The vital role of T404 phosphorylation of STAT2 in post-viral bacterial pneumonia

> **NIH NIH R56** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $402,500

## Abstract

PROJECT SUMMARY
Virus-associated 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 T404 phosphorylation of STAT2, stimulated by virus infections, enabling an efficient antiviral
response in infected cells. This proposal sheds new light on the role of STAT2 T404 phosphorylation in the
pathogenesis of post-viral bacterial pneumonia from three perspectives: (1) the action of IFN: In response to viral
infection, IFN-I is produced to limit viral dissemination, but with enigmatic functions in the subsequent bacterial
infection, due to suppressing chemokine production, IL-17-dependent immune responses, and recruitment of
macrophages. Considering the positive regulation of T404 phosphorylation in IFN-I signaling, STAT2 will
compromise the integrity of lung barriers in post-viral bacterial pneumonia; (2) the regulation of inflammation:
We reported that the presence of STAT2 augments the production of IL-6 and other NF-kB-dependent
inflammatory cytokines in response to LPS. This subset of cytokines drives inflammation-associated lung injury.
In agreement with this finding, our preliminary data show that STAT2 T404 phosphorylation-deficient mice are
protected from a challenge with LPS, compared with wild-type siblings. (3) STING-mediated antibacterial
functions of macrophages: By detecting bacterial-derived cyclic dinucleotides, STING mediates the antibacterial
functions of macrophages, including cytokine production, and bacterial digestion. We found that T404
phosphorylation mediates pervasive functions of STAT2 in STING activation, including reshaping STING-
mediated gene expression to a pro-inflammatory profile, and inhibiting subsequent outcomes, including bacterial
clearance. In summary, we propose that T404 phosphorylation of STAT2 is a key event, induced by virus
infection, that enhances IFN-I-dependent signaling, exaggerates inflammatory-associated acute lung
injury, and compromises antibacterial functions of macrophages in secondary bacterial pneumonia. This
proposal will carry our understanding from structural and mechanistic analyses forward to phenotypic changes
in vitro and in vivo. We will also determine the kinetics of T404 phosphorylation of STAT2 in mice with post-
influenza P. aeruginosa pneumonia, and validate the findings in macrophages from patients with ARDS-
associated pneumonia. Successful completion of this proposal wi...

## Key facts

- **NIH application ID:** 10683783
- **Project number:** 1R56HL160639-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** YUXIN WANG
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10683783

## Citation

> US National Institutes of Health, RePORTER application 10683783, The vital role of T404 phosphorylation of STAT2 in post-viral bacterial pneumonia (1R56HL160639-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10683783. Licensed CC0.

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