# Molecular Mechanisms of Inflammasome Activation During Salmonella Infections

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $384,014

## Abstract

PROJECT SUMMARY
Mammals have evolved a number of innate immune defense mechanisms to detect microbial infection and
protect the host. Previous studies of have demonstrated that intracellular multiprotein complexes, called
inflammasomes, are important for host defense against infections. Inflammasomes sense infectious or noxious
stimuli and activate effector proteases caspase-1 (casp-1) and caspase-11 (casp-11). Casp-1 processes pro-
inflammatory cytokines IL-1band IL-18 to contribute to pathogen control. Casp-11 detects cytosolic
lipopolysaccharide (LPS) and activates a pro-inflammatory cell death pathway termed pyroptosis when host
cells are infected with Gram-negative pathogens or during septic shock induced by LPS. An increased
understanding of how casp-11 is regulated during Gram-negative bacterial infections is necessary in order to
develop new therapeutics to treat these infections.
We have used Salmonella enterica serovars, which cause diseases ranging from self-limited gastroenteritis
(e.g., S. Typhimurium) to systemic infections (e.g., S. Typhi) in humans, as a model Gram-negative pathogen
to elucidate the molecular mechanisms of inflammasome activation. We have shown that intracellular S.
Typhimurium (Stm) induce casp-11-dependent macrophage death, which is due to leakage of LPS from the
Salmonella containing vacuole (SCV) into the macrophage cytosol. In ongoing experiments, we have found
that casp-11 is regulated by both host and pathogen factors. Our preliminary data show that: (1) mouse
complement factors regulate casp-11 gene expression, (2) two different casp-11 transcript variants, in addition
to the full-length transcript, occur in macrophages treated with LPS, and (3) at least one Stm virulence factor
that is translocated into host cells by a type 3 secretion system (T3SS) dampens the activation of casp-11
inflammasomes. These data suggest that the innate immune detection of intracellular Gram-negative bacteria
and LPS that leads to casp-11 activation is regulated by the host at multiple levels (e.g., gene transcription,
multiple casp-11 variants) and by Stm virulence factors.
Given these findings, we hypothesize that specific host proteins direct casp-11 cell death and that Salmonella
virulence factors modulate casp-11 activation. These hypotheses will be addressed in the experiments of the
following Specific Aims: (1) identify host molecules and pathways involved in casp-11-dependent cell death, (2)
characterize the expression and function of casp-11 transcript variants in the context of bacterial infection, and
(3) identify Salmonella factors that impact casp-11-dependent cell death.
The result of this study will lead to the identification and characterization of new host and bacterial factors that
regulate casp-11 during bacterial infections. These findings may lead to novel therapeutics for the treatment of
infections with Gram-negative pathogens and sepsis.

## Key facts

- **NIH application ID:** 9961473
- **Project number:** 5R01AI095396-09
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Denise M Monack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,014
- **Award type:** 5
- **Project period:** 2011-12-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961473

## Citation

> US National Institutes of Health, RePORTER application 9961473, Molecular Mechanisms of Inflammasome Activation During Salmonella Infections (5R01AI095396-09). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/9961473. Licensed CC0.

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