# A New IFN-γ Activated Cell Death Pathway in Salmonella-infected Non-Phagocytic Cells

> **NIH NIH R21** · RESEARCH INST OF FOX CHASE CAN CTR · 2020 · $274,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Salmonella species (especially the S. enterica serotypes typhi and typhimurium) cause disease in ~90 million
people every year worldwide. Salmonella infects both phagocytic immune cells (such as macrophages), as well
as non-phagocytic cells. When Salmonella infects macrophages, it triggers a rapid, pro-inflammatory form of
death called pyroptosis. Unlike the case with macrophages, less is known about Salmonella-triggered cell death
responses in non-phagocytic cells, such as intestinal epithelial cells and fibroblasts. As these are the some of
the first cell types infected by Salmonella, understanding how they respond to this bacterium, and whether
pyroptotic clearance mechanisms are at play in these cells, is an important objective. Our preliminary data
demonstrate that infecting epithelial and fibroblastic cells with Salmonella and later exposing them to IFN-
γ, mimicking the environment of infection in the intestine, induces a novel form of cell death that is neither
pyroptosis nor any of the other reported mechanisms of programmed cell death, including apoptosis, necroptosis,
or autophagy. Mechanistically, we find that IFN-γ ruptures the Salmonella-containing vacuole in non-phagocytic
cells, releasing Salmonella into the cytosol, from where the bacterium induces cell death. Results from a CRISPR
screen suggest that such cell death is the consequence of toxified mitochondria. Based on these and other
observations, we hypothesize that IFN-γ-induced cell death in non-phagocytic cells is a host defense mechanism
that destroys infected intestinal epithelial cells to limit Samonella spread in vivo. To test this hypothesis, we have
generated mice in which IFN-γ signaling can be selectively ablated in either intestinal epithelial cells or
phagocytes. The Aims of this proposal are to (1) elucidate the mechanism by which Salmonella kills non-
phagocytic cells upon IFN-γ exposure; and (2) test the in vivo role of IFN-γ signaling and cell death in Salmonella-
infected intestinal epithelial cells during acute Salmonella infection. The successful completion of these Aims will
reveal the mechanism and in vivo role of a IFN-γ-driven new death pathway engaged by the host during anti-
Salmonella immune responses.

## Key facts

- **NIH application ID:** 9964656
- **Project number:** 5R21AI142114-02
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** SIDDHARTH BALACHANDRAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $274,500
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964656

## Citation

> US National Institutes of Health, RePORTER application 9964656, A New IFN-γ Activated Cell Death Pathway in Salmonella-infected Non-Phagocytic Cells (5R21AI142114-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9964656. Licensed CC0.

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