# Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2022 · $243,750

## Abstract

Project Summary
Macrophages infected by Salmonella enterica serovar Typhimurium (STm) undergo a lytic inflammatory cell
death known as pyroptosis to eliminate Salmonella’s replicative niche and promote inflammatory responses via
release of IL-1 cytokines. While STm SPI-1 activity triggers a rapid Casp1-dependent pyroptosis, it can still
induce Caspase-8 (Casp-8)-dependent cell death in the absence of Casp1. However, in the absence of SPI-1-
mediated invasion and early pyroptosis, STm establishes a replicative compartment within macrophages and
triggers a late Casp1/11-dependent cell death. Intriguingly, our preliminary studies show for the first time that in
contrast to STm strains that have previously been studied, clinical S. enterica serovar isolates, including S.
Enteritidis (SE), obtained from a strain bank of veterinary isolates at the University of Pennsylvania, and DT104,
the recently-emerged STm strain responsible for invasive non-Typhoidal Salmonella (iNTS) disease in sub-
Saharan Africa, trigger Casp1/11-independent cell death, suggesting that the innate immune response to clinical
Salmonella enterica differs significantly from that induced by commonly used laboratory strains. SE is a leading
cause of Salmonellosis in the United States, yet we currently lack mechanistic knowledge of how it interacts with
the innate immune system. The central goal of this proposal is to define the host and Salmonella factors
responsible for late Casp1/11-independent death, which may contribute to the pathogenesis of invasive disease
caused by iNTS isolates. We find that Casp8 is responsible for the Casp1/11-independent cell death triggered
by SE infection, and that this cell death requires a functional SPI-2 T3SS. Together, our studies provoke the
hypothesis that Salmonella serovar Enteritidis possesses unique virulence factors that trigger Casp8-mediated
cell death in the absence of Casp1. We will test this hypothesis in this proposal in two Aims that will (1) Define
the host signaling components required to induce Casp8-dependent cell death in response to SE, and (2)
Mechanistically define the SE-specific bacterial factors required to induce this SPI-2- and Casp8-dependent cell
death. Defining such factors will provide new insight into the virulence and host interactions of less well-studied
Salmonella serovars that are responsible for a large proportion of Salmonella infections in the US and Europe.

## Key facts

- **NIH application ID:** 10452195
- **Project number:** 1R21AI163596-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** IGOR E BRODSKY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,750
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452195

## Citation

> US National Institutes of Health, RePORTER application 10452195, Defining mechanisms of Casp1/11-independent death triggered by clinical Salmonella Enteritidis (1R21AI163596-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10452195. Licensed CC0.

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