We 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 S. typhimurium infection. The long-term goal of this research application is to understand how the host recognizes intracellular S. typhimurium and how this pathogen has evolved to subvert innate immune defenses. We have demonstrated that multiple host cytosolic sensors are involved in recognizing intracellular S. typhimurium and activating the inflammasome. In addition, we have shown that multiple caspase-1 complexes are formed in response to intracellular S. typhimurium.
In Aim1, we will use genetic and biochemical approaches to identify new host molecules and pathways involved in caspase- 1-dependent maturation and release of pro-inflammatory cytokines.
In Aim 2, we will take biochemical and genetic approaches to identify host molecules and pathways involved in caspase-1-induced macrophage death.
In Aim 3, we will characterize the spatial and temporal relationships between caspase-1 complex formation, cytokine release and host cell death. 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

The proposed research is relevant to public health because an increased understanding of the mechanisms that lead to the activation of the inflammasome when our immune system recognizes intracellular bacterial pathogens, such as Salmonella, will lead to novel therapeutic avenues. Thus, the proposed research is relevant to NIH's mission that pertains to developing fundamental knowledge that will 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 #
5R01AI095396-03
Application #
8582059
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$328,440
Indirect Cost
$118,440
Name
Stanford University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Ng, Tessie M; Kortmann, Jens; Monack, Denise M (2013) Policing the cytosol--bacterial-sensing inflammasome receptors and pathways. Curr Opin Immunol 25:34-9
Broz, Petr; Monack, Denise M (2013) Measuring inflammasome activation in response to bacterial infection. Methods Mol Biol 1040:65-84
Broz, Petr; Monack, Denise M (2013) Newly described pattern recognition receptors team up against intracellular pathogens. Nat Rev Immunol 13:551-65
Eisele, Nicholas A; Ruby, Thomas; Jacobson, Amanda et al. (2013) Salmonella require the fatty acid regulator PPARýý for the establishment of a metabolic environment essential for long-term persistence. Cell Host Microbe 14:171-82
Ng, Tessie M; Monack, Denise M (2013) Revisiting caspase-11 function in host defense. Cell Host Microbe 14:9-14
Broz, Petr; Monack, Denise M (2013) Noncanonical inflammasomes: caspase-11 activation and effector mechanisms. PLoS Pathog 9:e1003144