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The Molecular Mechanism and Pathophysiology of Robust STAT3 Signaling During Oral Salmonella Typhimurium Infection

Award Number: F31AI176719
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Abstract Salmonella enterica serovar Typhimurium is the causative agent of salmonellosis, leading to ~150 million cases of gastroenteritis annually around the world, making it one of the most common foodborne diseases. Salmonella enterica serovars are especially reliant on secreted protein effectors for virulence. These effectors can mimic and reprogram host cellular functions to create a beneficial environment for the invading bacteria, such as formation of the intracellular salmonella containing vacuole (SCV) and antagonization of the immune response. My lab previously found that increased intracellular replication of S. Typhimurium and production of anti-inflammatory cytokine interleukin-10 (IL-10) by host cells is associated with the secreted protein effector SarA. SarA acts through host STAT3 (signal transducer and activator of transcription) signaling by mimicking the function of host cytokine receptor gp130. However, despite homology between SarA and gp130, I have shown that SarA leads to greater STAT3 phosphorylation over a longer period of time than gp130. Previous research in the field of STAT3 signaling suggests that the kinetics of STAT3 activation have a dramatic effect on whether the downstream transcriptional targets are pro- or anti-inflammatory. I hypothesize that S. Typhimurium effector SarA evolved molecular characteristics to hijack and prolong host STAT3 signaling to promote important anti-inflammatory responses during acute infection in the gut. I propose mutagenizing SarA and measuring how these manipulations alter 1) SarA binding to STAT3 and negative regulators, 2) SarA-directed phosphorylation of STAT3, 3) expression of downstream transcriptional targets and 4) SarA-associated burden and IL-10 phenotypes in cells and mice. My lab has previously shown that SarA leads to increased STAT3 phosphorylation and fitness in systemic sites (spleen, liver) during intraperitoneal (I.P.) and chronic murine infection models. However, neither of these models represent the natural oral infection route of S. Typhimurium in humans. I have shown that wild-type and complemented Salmonella Typhimurium have ~100x greater burden in the small intestine compared to ∆sarA during infection in an oral murine model. I will further elucidate the mechanism by which SarA signaling acts on the mucosal immune responses to benefit S. Typhimurium during oral infection. This proposal aims to understand the molecular basis for robust STAT3 activation by SarA, and how S. Typhimurium hijacking of the host STAT3 signaling pathway impacts infection outcome during intestinal infection in vivo.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $42,327 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	1/14/2025	NON-COMPETING CONTINUATION	$42,327
														Subtotal = $42,327

Issue Date FY: 2024 ( Subtotal = $41,621 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	1/23/2024	NEW	$40,341
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	1	1/23/2024	NEW	$0
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	002	1	5/8/2024	NEW	$1,280
														Subtotal = $41,621

Grand Total All Awards = $83,948

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The Molecular Mechanism and Pathophysiology of Robust STAT3 Signaling During Oral Salmonella Typhimurium Infection

Award Number: F31AI176719

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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