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Determining the Mechanism of TNF in Defense Against Intracellular Bacterial Infection

确定 TNF 防御细胞内细菌感染的机制

基本信息

批准号：
10229609
负责人：
Tzvi Pollock
金额：
$ 3.34万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229609
关键词：
Adaptor Signaling Protein Alveolar Alveolar Macrophages Anti-Bacterial Agents Apoptosis Apoptotic Bacteria Bacterial Infections Bone Marrow CASP8 gene Caspase Cell Death Cell Survival Cells Dangerousness Data Defect Development Disease Etiology Family member Gene Expression Growth Host Defense Immune In Vitro Induction of Apoptosis Infection Inflammation Inflammatory Inflammatory Response Inhalation Innate Immune System Interleukin-1 beta Interleukin-6 Invaded Legionella Legionella pneumophila Legionnaires&apos Disease Lung MAPK8 gene Mediating Mitogen-Activated Protein Kinases Molecular Morbidity - disease rate Multi-Drug Resistance Mus Outcome Pathogenicity Pathologic Pathway interactions Phagocytes Phosphotransferases Predisposition Principal Investigator Process Production Proliferating RIPK1 gene Research Research Personnel Rheumatoid Arthritis Risk Role Signal Transduction TNF gene Techniques Testing Therapeutic Type IV Secretion System Pathway Ubiquitination Ulcerative Colitis United States Up-Regulation Vacuole Yersinia infections antimicrobial burden of illness combat cytokine defined contribution genetic approach improved in vivo infection risk inhibitor/antagonist insight macrophage microorganism mortality p38 Mitogen Activated Protein Kinase pathogen pathogenic bacteria receptor response scaffold skills therapeutic target

项目摘要

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.

项目总结