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
Sastalla, Inka; Monack, Denise M; Kubatzky, Katharina F (2016) Editorial: Bacterial Exotoxins: How Bacteria Fight the Immune System. Front Immunol 7:300
Napier, Brooke A; Monack, Denise M (2016) IMMUNOLOGY. A lipid arsenal to control inflammation. Science 352:1173-4
Napier, Brooke A; Brubaker, Sky W; Sweeney, Timothy E et al. (2016) Complement pathway amplifies caspase-11-dependent cell death and endotoxin-induced sepsis severity. J Exp Med 213:2365-2382
Carden, Sarah; Okoro, Chinyere; Dougan, Gordon et al. (2015) Non-typhoidal Salmonella Typhimurium ST313 isolates that cause bacteremia in humans stimulate less inflammasome activation than ST19 isolates associated with gastroenteritis. Pathog Dis 73:
Storek, Kelly M; Gertsvolf, Nina A; Ohlson, Maikke B et al. (2015) cGAS and Ifi204 cooperate to produce type I IFNs in response to Francisella infection. J Immunol 194:3236-45
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
Storek, Kelly M; Monack, Denise M (2015) Bacterial recognition pathways that lead to inflammasome activation. Immunol Rev 265:112-29
O'Donnell, Hope; Pham, Oanh H; Li, Lin-xi et al. (2014) Toll-like receptor and inflammasome signals converge to amplify the innate bactericidal capacity of T helper 1 cells. Immunity 40:213-24
Gopinath, Smita; Lichtman, Joshua S; Bouley, Donna M et al. (2014) Role of disease-associated tolerance in infectious superspreaders. Proc Natl Acad Sci U S A 111:15780-5
Ng, Tessie M; Monack, Denise M (2013) Revisiting caspase-11 function in host defense. Cell Host Microbe 14:9-14

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