We use a S. typhimurium (Stm) mouse model to study Salmonella-host interactions and have shown that the mammalian inflammasome, an innate immune protective complex that mediates a pro- inflammatory host response, is important for controlling Stm infection. The long-term goal of this research application is to understand how the host recognizes intracellular Stm and how this pathogen has evolved to subvert innate immune defenses. We have demonstrated that multiple host cytosolic receptors are involved in recognizing intracellular Stm and activating the inflammasome.
In Aim1, we will use genetic approaches to identify new bacterial factors that contribute to pro-inflammatory cytokine release and caspase-1 activation.
In Aim 2, we will take biochemical and genetic approaches to identify host molecules and pathways involved in caspase-1 and cytokine maturation and release.
In Aim 3, we will characterize the role of the host cytosolic receptors identified in Aim 2 that are important for caspase-1-dependent cytokine release or macrophage death during murine infection with Stm. These studies are aimed at gaining a better understanding of the molecular mechanisms of intracellular recognition, which will lead to the rational design of therapeutics that will benefit public health.

Public Health Relevance

Salmonellosis constitutes a major public health burden with millions of human cases every year and the disease results in thousands of deaths. Our proposed studies are aimed at gaining a better understanding of the molecular mechanisms of intracellular bacterial pathogen recognition and inflammation and may lead to improved therapeutics and vaccines.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI089722-04
Application #
8701223
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
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Kortmann, Jens; Brubaker, Sky W; Monack, Denise M (2015) Cutting Edge: Inflammasome Activation in Primary Human Macrophages Is Dependent on Flagellin. J Immunol 195:815-9
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Ng, Katharine M; Ferreyra, Jessica A; Higginbottom, Steven K et al. (2013) Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502:96-9
Broz, Petr; Monack, Denise M (2013) Noncanonical inflammasomes: caspase-11 activation and effector mechanisms. PLoS Pathog 9:e1003144
Eisele, Nicholas A; Ruby, Thomas; Jacobson, Amanda et al. (2013) Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence. Cell Host Microbe 14:171-82
Ng, Tessie M; Kortmann, Jens; Monack, Denise M (2013) Policing the cytosol--bacterial-sensing inflammasome receptors and pathways. Curr Opin Immunol 25:34-9

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