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

项目摘要 细胞内的细菌病原体，如嗜肺军团菌，严重肺炎的病原体 肺炎军团病，是美国每年造成重大疾病负担的疾病之一 年。成功控制军团菌和其他细胞内细菌病原体需要强大的免疫力 允许产生炎性细胞因子的反应，如肿瘤坏死因子 使巨噬细胞能够限制细胞内的细菌复制。宿主防御需要肿瘤坏死因子 军团菌和其他病原体在小鼠模型中的感染。肿瘤坏死因子对军团菌的控制也至关重要 以及其他细胞内病原体，因为患者服用肿瘤坏死因子阻滞剂治疗炎症性疾病 例如类风湿性关节炎或溃疡性结肠炎患退伍军人症的风险增加，以及 其他细菌感染。然而，肿瘤坏死因子介导的确切分子和细胞机制 抗菌防御仍不清楚。我们的新的初步数据表明，肿瘤坏死因子促进caspase-8- 军团菌感染过程中依赖的细胞死亡，以及缺乏caspase-8的小鼠和巨噬细胞 在控制军团菌感染方面存在缺陷。这些新数据引发了一种假设，即肿瘤坏死因子促进 依赖caspase-8的巨噬细胞凋亡抑制军团菌感染。因此，目标1寻求 验证肿瘤坏死因子诱导caspase-8介导的感染巨噬细胞死亡的假说 细胞内细菌复制。目的2将测试假设，肿瘤坏死因子和半胱氨酸天冬氨酸氨基转移酶-8介导的死亡 感染的肺泡巨噬细胞促进宿主控制肺军团菌感染。这些研究将 提供了关于肿瘤坏死因子如何介导细胞内细菌感染的免疫控制的基本见解，并可能 为开发治疗军团菌和其他疾病的改进疗法提供依据 细菌感染。

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.