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.

Public Health Relevance

The cytokine TNF is critical for host immune control of infections caused by intracellular pathogens such as Legionella pneumophila, causative agent of Legionnaires' disease and an important cause of community- and hospital-acquired pneumonia. This proposal aims to determine how TNF defends against Legionella. This information will allow for the development of better therapeutics for the treatment of bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI151476-01A1
Application #
10128616
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ernst, Nancy L
Project Start
2021-03-05
Project End
2023-02-28
Budget Start
2021-03-05
Budget End
2022-02-28
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104