# STAT3-dependent manipulation of host transcription and immune responses by Salmonella

> **NIH NIH F31** · DUKE UNIVERSITY · 2020 · $37,622

## Abstract

Project Summary/Abstract
Background: Across the globe, non-typhoidal serovars of the intracellular bacterial pathogen
Salmonella enterica caused 153 million cases of gastroenteritis and 57,000 deaths in 2010. S.
enterica enterica ser. Typhimurium, the most prevalent non-typhoidal Salmonella (NTS) serovar,
creates a durable niche inside host cell vacuoles by injecting effector proteins that subvert host
signal transduction pathways. Recently, S. Typhimurium has been shown to promote its
intracellular survival and replication by activating the host transcription factor STAT3. While
STAT3 is known to promote cell differentiation, survival, and proliferation in response to cytokines
and growth factors, it is unknown how Salmonella drives STAT3 phosphorylation or how STAT3
renders host cells more permissive to S. Typhimurium.
Goal/Preliminary Data: I aim to understand the mechanism and function of STAT3
phosphorylation during Salmonella infection. Recently, our lab discovered that an S. Typhimurium
effector, SarA, physically associates with STAT3 and induces STAT3 phosphorylation. However,
SarA lacks identifiable structural homology to any known kinase domain, so I hypothesize that
SarA initiates a signaling pathway to phosphorylate STAT3. Further, S. Typhimurium ∆sarA
exhibits reduced intracellular replication in human cells and infected mice. This SarA-dependent
reduction is recapitulated by knockdown or inhibition of host STAT3 during wild-type infection,
indicating that SarA promotes virulence by activating STAT3. Hence, I hypothesize that STAT3-
targets promote bacterial replication in the Salmonella-containing vacuole (SCV).
Approach: I will determine how SarA-interacting partners, identified by proteomics, interact with
phosphorylated SarA motifs to drive STAT3 tyrosine phosphorylation. In parallel, I will verify
potential SarA to STAT3 signaling components or regulators that were identified through common
human genetic variants associated with the level of STAT3-target activation. Finally, I will
determine how activated STAT3 promotes S. Typhimurium intracellular replication, by
ascertaining how SarA-dependent transcriptional changes, identified by transcriptomics analysis,
promote intracellular bacterial replication.
Significance: Uncovering how S. Typhimurium activates STAT3 to manipulate host transcription
and improve its intracellular niche will enhance our understanding of bacteria-host interaction and
the function of the STAT3 pathway, a crucial player in autoimmunity and oncogenesis.

## Key facts

- **NIH application ID:** 9863743
- **Project number:** 5F31AI136313-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Kyle Dane Gibbs
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,622
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9863743

## Citation

> US National Institutes of Health, RePORTER application 9863743, STAT3-dependent manipulation of host transcription and immune responses by Salmonella (5F31AI136313-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9863743. Licensed CC0.

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