# SALMONELLA HIJACKING OF STAT3 AND CONSEQUENCES FOR DISEASE

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $193,903

## Abstract

Salmonellae cause an estimated 150 million cases of gastroenteritis and 25 million cases of invasive disease
(enteric fever and non-typhoidal bacteremia), leading to 300,000 deaths per year. Salmonella manipulates
multiple host cellular pathways through secreted effector proteins, but the molecular functions of most effectors,
especially in animals and humans, remain poorly understood. A thorough characterization of how Salmonella
effectors function and the pathways they target is required to understand how effectors impact infection and their
long-term consequences on chronic inflammatory conditions, such as inflammatory bowel disease (IBD). IBD is
an immune-mediated disease and whether IBD is affected by previous Salmonella infection is unclear, with
conflicting evidence from both epidemiological and mouse studies. To understand how acute Salmonella
infections may impact long-term immune modulation, studies are needed to determine how specific Salmonella
effectors target host immune regulatory pathways, whether these changes persist beyond infection, and if these
changes modulate risk or severity of disease.
Through comparative genomics of Salmonella serovars, we recently identified a novel prophage-encoded Type
III secreted effector: Salmonella anti-inflammatory response activator (SarA). SarA is the only Salmonella
effector demonstrated to be necessary and sufficient to activate STAT3 (signal transducer and activator of
transcription-3), a key transcription factor that regulates immune cell proliferation, development, and autoimmune
conditions including IBD. SarA-mediated manipulation of STAT3 reprograms transcription in host cells and
increases virulence in mice. We hypothesize SarA has both direct effects on cells injected with the effector and
secondary consequences due to STAT3 target genes (such as the anti-inflammatory cytokine IL-10) that may
cause persistent changes after infection has cleared. Therefore, the objective of this application is to
determine how SarA activates STAT3 and affects immune cell populations during and after infection.
Based on preliminary data, we hypothesize that SarA directly binds STAT3 and cofactors to assemble a STAT3-
activating platform. Activation of this pathway phosphorylates STAT3 in multiple cell types, but it is unknown
which cells are targeted in vivo and what the consequences of this activation are during and after infection.
Therefore, we propose Specific Aims to 1) determine how SarA drives STAT3 activation through biochemical
and genetic approaches and 2) determine the effects of SarA on immune cell populations and long-term
consequences for the host, including severity of intestinal inflammation in colitis. Following completion of these
aims, we will have determined how SarA mediates STAT3 signaling and how/if these signaling events alter
immune function during and after infection. Revealing these mechanisms could lead to new therapeutic
strategies for treating salmonellosis, as well as other...

## Key facts

- **NIH application ID:** 9962292
- **Project number:** 5R21AI146520-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Dennis Chun-Yone Ko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,903
- **Award type:** 5
- **Project period:** 2019-06-21 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962292

## Citation

> US National Institutes of Health, RePORTER application 9962292, SALMONELLA HIJACKING OF STAT3 AND CONSEQUENCES FOR DISEASE (5R21AI146520-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962292. Licensed CC0.

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