Innate Immune Detection of Intracellular Pathogens

描述（由申请人提供）：本提案的总体目标是了解哺乳动物细胞如何检测细胞内病原体的存在。Dietrich实验室最近的遗传证据表明，小鼠13号染色体上的一个新基因（Birc1e）是巨噬细胞对新出现的细胞内病原体嗜肺军团菌的抗性所必需的。Birc1e保护巨噬细胞的机制是完全未知的，似乎是新的。然而，有趣的是，Birc1e含有一个富含亮氨酸的重复序列（LRR）结构域，也存在于其他病原体检测蛋白中，如toll样受体和Nod蛋白家族。我们建议Birc1e利用其LRR直接或间接检测特定的军团菌产物。在本提案中，我的目标是鉴定该产物并确定Birc1e如何协调免疫防御以保护细胞免受嗜肺乳杆菌的侵害。这些研究不仅揭示了一种新兴感染性微生物的发病机制，而且还可能提供对先天免疫系统如何检测和防御感染的见解，从而为我们如何设计更好的病原体检测和防御系统提供线索。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand how mammalian cells detect the presence of intracellular pathogens. Recent genetic evidence from the Dietrich Lab has shown that a novel gene on mouse chromosome 13 (Birc1e) is required for resistance of macrophages to the emerging intracellular pathogen, Legionella pneumophila. The mechanism by which Birc1e protects macrophages is completely unknown and appears to be novel. Interestingly, however, Birc1e contains a leucine-rich repeat (LRR) domain also present in other pathogen-detector proteins such as Toll-like Receptors and the Nod family of proteins. We propose that Birc1e employs its LRR to detect, directly or indirectly, a specific Legionella product. In this proposal, I aim to identify this product and determine how Birc1e orchestrates immune defenses to protect cells from L. pneumophila. These studies should not only shed light on the pathogenetic mechanisms of an emerging infectious microbe, but might also provide insight into how the innate immune system detects and defends against infection, thereby providing clues as to how we may design better pathogen detection and defense systems ourselves.