# TNF and caspase-8-mediated control of Legionella pneumophila infection

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2021 · $202,917

## Abstract

Project Summary
Intracellular bacterial pathogens such as Legionella pneumophila, the causative agent of the severe
pneumonia Legionnaires' disease, are responsible for significant disease burden in the United States every
year. Successful control of Legionella and other intracellular bacterial pathogens requires a robust immune
response that allows for production of inflammatory cytokines, such as Tumor Necrosis Factor (TNF), that
enables macrophages to restrict intracellular bacterial replication. TNF is required for host defense against
Legionella and other pathogens in mouse models of infection. TNF is also critical for the control of Legionella
and other intracellular pathogens in humans, as patients taking TNF blockers to treat inflammatory disorders
such as rheumatoid arthritis or ulcerative colitis are at increased risk of acquiring Legionnaires' disease and
other bacterial infections. However, the precise molecular and cellular mechanisms by which TNF mediates
anti-bacterial defense are still unclear. Our new preliminary data indicate that that TNF promotes caspase-8-
dependent cell death during Legionella infection, and that mice and macrophages deficient for caspase-8 are
defective in controlling Legionella infection. These new data provoke the hypothesis that TNF promotes
caspase-8-dependent apoptosis of infected macrophages to restrict Legionella infection. Thus, Aim 1 seeks to
test the hypothesis that TNF induces caspase-8-mediated death of infected macrophages to restrict
intracellular bacterial replication. Aim 2 will test the hypothesis that TNF- and caspase-8-mediated death of
infected alveolar macrophages promotes host control of pulmonary Legionella infection. These studies will
provide fundamental insight into how TNF mediates immune control of intracellular bacterial infection, and may
provide a basis for the development of improved therapeutics for the treatment of Legionella and other
bacterial infections.

## Key facts

- **NIH application ID:** 10128616
- **Project number:** 1R21AI151476-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sunny Shin
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $202,917
- **Award type:** 1
- **Project period:** 2021-03-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128616

## Citation

> US National Institutes of Health, RePORTER application 10128616, TNF and caspase-8-mediated control of Legionella pneumophila infection (1R21AI151476-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10128616. Licensed CC0.

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