We study Salmonella-host interactions and have shown that a host regulator of fatty acid metabolism, PPAR?, controls persistent systemic S. Typhimurium infection in mice. PPAR?, a transcriptional factor that plays a role in regulating metabolic and immune pathways, is specifically upregulated in Salmonella- infected macrophages. Importantly, PPAR?-deficient mice are not chronically infected with S. Typhimurium. The long-term goal of this research proposal is to understand how S. Typhimurium usurps and manipulates host metabolic and immune activities during chronic infection.
In Aim 1, we will use genetic and biochemical approaches to identify mechanisms of Salmonella-dependent activation of PPAR?.
In Aim 2, we will identify the PPAR?-dependent immune and metabolic pathways required for Salmonella replication in macrophages.
In Aim 3, we will use germ-free mice and mice deficient for PPAR? in macrophages or gut epithelial cells to characterize PPAR?-dependent mechanisms of Salmonella persistence in the gastrointestinal tract. These studies are aimed at gaining a better understanding of the molecular mechanisms of host-pathogen interactions during chronic infections, which will lead to the rational design of therapeutics that will benefit public health.

Public Health Relevance

The proposed research is relevant to public health. An increased understanding of the mechanisms that lead to persistent Salmonella infections within macrophages and the gastrointestinal tract will lead to novel therapeutic avenues. Thus, the proposed research is relevant to NIH's mission that pertains to developing fundamental knowledge to reduce the burdens of human infectious disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116059-02
Application #
8959619
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Alexander, William A
Project Start
2014-11-01
Project End
2019-10-31
Budget Start
2015-11-01
Budget End
2016-10-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Sana, Thibault G; Flaugnatti, Nicolas; Lugo, Kyler A et al. (2016) Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut. Proc Natl Acad Sci U S A 113:E5044-51