The molecular mechanism and pathophysiology of robust STAT3 signaling during oral salmonella typhimurium infection

Active Project Grant Awarded Last action

Award ID
F31AI176719
Recipient
Awarding agency
Obligated
$337,730

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 90% complete
Place of performance
Durham, NC 27710, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $576
Amendment $43,442
Amendment $43,442
Amendment $564
Amendment $564
Amendment $564
Amendment $42,327
Amendment $42,327
Amendment $1,280
Amendment $1,280
Amendment $40,341
Amendment $40,341
Amendment $0
Amendment $0
Amendment $40,341
Amendment $40,341
Original award $0
Show all 17

Quick answers

Who received award F31AI176719?

F31AI176719 was awarded to Duke University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 31, 2024.

How much is award F31AI176719 worth?

$337,730 has been obligated on F31AI176719.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login