# Determining the Mechanism of TNF in Defense Against Intracellular Bacterial Infection

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $33,374

## Abstract

Project Summary
Intracellular bacterial pathogens such as Legionella pneumophila, the causative agent of Legionnaires’ Disease,
are responsible for significant disease burden in the United States every year. Successful control of these
pathogens is reliant on the inflammatory cytokine Tumor Necrosis Factor (TNF). TNF is responsible for the
upregulation of innate immune activity, and directs the inflammatory response. Therapeutics targeting TNF
signaling are common in treatment of inflammatory disorders such as rheumatoid arthritis or ulcerative colitis;
however, these therapeutics carry with them an increased susceptibility to intracellular bacterial infection. TNF
has proven a critical factor in defense against Legionella and other intracellular pathogens, and the molecular
details of TNF signaling are well characterized. The downstream effects of TNF, however, are diverse – ranging
from promoting cell survival to triggering programmed cell death – and thus the precise mechanisms through
which TNF mediates anti-bacterial defense are still unclear.
 Our new preliminary data indicate that, upon Legionella infection, TNF is required for optimal
inflammatory cytokine production in bone marrow-derived macrophage (BMDM) culture. The mechanism by
which TNF promotes cytokine production during Legionella infection is unknown. Furthermore, we present new
additional data showing that mice and cells deficient for the apoptotic caspase, Caspase-8, possess a defect in
control of Legionella infection that cannot be rescued by exogenous rTNF treatment, suggesting that TNF’s
downstream mechanism may be related to the induction of apoptosis of infected host cells.
 Thus, Aim 1 seeks to test the hypothesis that pro-survival and inflammatory signaling serves to upregulate
the production of protective cytokines by infected cells. Aim 2 seeks to test the hypothesis that TNF-dependent
apoptotic signaling in infected cells acts to restrict the replicative niche of the bacteria and thus limit growth and
spread. This research 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 that dampen
pathological inflammation without increased risk of infection.

## Key facts

- **NIH application ID:** 10229609
- **Project number:** 5F31AI140508-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Tzvi Pollock
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,374
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229609

## Citation

> US National Institutes of Health, RePORTER application 10229609, Determining the Mechanism of TNF in Defense Against Intracellular Bacterial Infection (5F31AI140508-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229609. Licensed CC0.

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