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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AI062017-01
Application #
6836718
Study Section
Special Emphasis Panel (ZRG1-F07 (20))
Program Officer
Korpela, Jukka K
Project Start
2004-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$50,548
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Coers, Jorn; Vance, Russell E; Fontana, Mary F et al. (2007) Restriction of Legionella pneumophila growth in macrophages requires the concerted action of cytokine and Naip5/Ipaf signalling pathways. Cell Microbiol 9:2344-57
Ren, Tao; Zamboni, Dario S; Roy, Craig R et al. (2006) Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog 2:e18
Zamboni, Dario S; Kobayashi, Koichi S; Kohlsdorf, Tiana et al. (2006) The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol 7:318-25