Innate Immune Detection of Intracellular Pathogens

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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.