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

• 批准号: 9760091
• 负责人: Tzvi Pollock
• 金额: $ 4.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/9760091
• 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; Genes; 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' 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; 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

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.

项目概要 细胞内细菌病原体，例如嗜肺军团菌，军团病的病原体， 每年都对美国造成重大疾病负担。成功控制这些 病原体依赖于炎症细胞因子肿瘤坏死因子（TNF）。 TNF 负责 上调先天免疫活性，并指导炎症反应。 TNF 靶向治疗 信号传导在类风湿性关节炎或溃疡性结肠炎等炎症性疾病的治疗中很常见； 然而，这些疗法对细胞内细菌感染的敏感性增加。肿瘤坏死因子 已被证明是防御军团菌和其他细胞内病原体的关键因素，并且分子 TNF 信号传导的细节已得到很好的表征。然而，TNF 的下游影响是多种多样的——范围广泛 从促进细胞存活到触发程序性细胞死亡——以及由此产生的精确机制 TNF 介导哪种抗菌防御尚不清楚。 我们新的初步数据表明，在军团菌感染时，TNF 是获得最佳效果所必需的。 骨髓源性巨噬细胞（BMDM）培养物中炎症细胞因子的产生。该机制由 哪种 TNF 在军团菌感染期间促进细胞因子的产生尚不清楚。此外，我们还推出了新 其他数据表明，缺乏凋亡 caspase（Caspase-8）的小鼠和细胞在 军团菌感染的控制不能通过外源性 rTNF 治疗来挽救，这表明 TNF 下游机制可能与诱导感染宿主细胞凋亡有关。 因此，目标 1 试图检验以下假设：促生存和炎症信号传导有助于上调 受感染细胞产生保护性细胞因子。目标 2 旨在检验 TNF 依赖性的假设 受感染细胞中的凋亡信号传导会限制细菌的复制生态位，从而限制生长和 传播。这项研究将为 TNF 如何介导细胞内免疫控制提供基础见解。 细菌感染，并可能为开发抑制细菌感染的改进疗法提供基础 病理性炎症而不增加感染风险。