Effector-triggered immunity against Legionella pneumophila in dendritic cells

项目摘要 细胞内细菌病原体，如嗜肺军团菌，严重肺炎的病原体 军团病是美国每年的重大疾病负担。的 越来越多的免疫抑制药物，特别是TNF阻断剂，用于治疗自身免疫性疾病， 显著增加细胞内细菌病原体（包括结核分枝杆菌）感染的风险 和嗜肺军团菌。越来越多的人功能性免疫功能低下 由于越来越多地使用TNF阻断剂，加上抗生素耐药性的日益蔓延， 公共卫生问题。我们的目标是确定TNF促进免疫防御的机制， 嗜肺军团菌这一信息可能使靶向治疗的发展，促进抗- 免疫受损个体的细菌防御。关键的是，在新的初步研究中， 我们有能力剖析军团菌和树突状细胞之间的相互作用，我们发现TNF信号驱动 一种军团菌效应子触发的免疫反应，诱导树突细胞凋亡，从而限制 细胞内军团菌复制。拟议的研究将提供基本的洞察如何TNF介导 效应子触发的免疫促进树突细胞内军团菌复制的控制。这 这些信息可能为开发治疗军团菌的改进疗法提供基础 和其他细菌病原体。

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. The growing use of immunosuppressive drugs, particularly TNF blockrs, to treat autoimmune diseases comes with a significantly increased risk of infection by intracellular bacterial pathogens, including Mycobacterium tuberculosis and Legionella pneumophila. The increasing numbers of individuals who are functionally immunocompromised due to growing use of TNF blockade, combined with the growing spread of antibiotic resistance, poses a serious public health concern. Our goal is to define the mechanisms by which TNF promotes immune defense against Legionella pneumophila. This information may enable development of targeted therapeutics that promote anti- bacterial defense in immunocompromised individuals. Critically, in new preliminary studies that take advantage of our ability to dissect the interactions between Legionella and dendritic cells, we find that TNF signaling drives a Legionella effector-triggered immune response that induces apoptosis in dendritic cells, thereby restricting intracellular Legionella replication. The proposed studies will provide fundamental insight into how TNF-mediated effector-triggered immunity promotes control of intracellular Legionella replication within dendritic cells. This information may provide a basis for the development of improved therapeutics for the treatment of Legionella and other bacterial pathogens.