The focus of this application is to determine how the mammalian immune system generates a response that provides protection against intracellular pathogens that replicate inside of specialized organelles. To gain novel insight into this process, this project has focused on determining the host mechanisms that provide protection against infection by the intracellular pathogen Legionella pneumophila. Host pattern recognition system controlled by the adapter proteins MyD88, Rip2, NLRC4, and Naip5 have been shown to trigger innate immune responses to L. pneumophila. The overall goal of this project is to determine how signals generated from these immune surveillance systems are integrated into a functional response that prevents lethal infection by L. pneumophila.
The aims of this project are to determine cell-specific responses in the lung by identifying host cells contain intracellular bacteria, host cells that have received L. pneumophila effector proteins translocated into the cytosol by the Dot/Icm system, and host cells that are producing proinflammatory signaling molecules in response to infection.
The second aim i s to determine the cell- specific roles for host pattern recognition systems in the pulmonary response to L. pneumophila using bone marrow chimeric mice and transgenic approaches.
The third aim i s to determine how spatial and temporal activation of the inflammasome restricts intracellular replication of L. pneumophila by investigating the mechanisms that underlie caspase-1 activation through NLRC4, Naip5 and ASC. These data will provide new details on how immune signals are received and propagated during infection by an intracellular pathogen.

Public Health Relevance

Intracellular pathogens represent a serious threat to human health, and to devise strategies to combat infections by these microbes a more detailed understanding of how the immune system responds to intracellular infection is needed. Thus, this project is focused on identifying molecular mechanisms that mediate host protection by investigating the role of immune surveillance pathways in generating a response against the intracellular pathogen Legionella pneumophila.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048770-14
Application #
8605823
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Minnicozzi, Michael
Project Start
2001-01-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
14
Fiscal Year
2014
Total Cost
$403,738
Indirect Cost
$161,253
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Marion, Chad R; Wang, Jianmiao; Sharma, Lokesh et al. (2016) Chitinase 3-Like 1 (Chil1) Regulates Survival and Macrophage-Mediated Interleukin-1β and Tumor Necrosis Factor Alpha during Pseudomonas aeruginosa Pneumonia. Infect Immun 84:2094-104
Bradley, William P; Boyer, Mark A; Nguyen, Hieu T et al. (2016) Primary Role for Toll-Like Receptor-Driven Tumor Necrosis Factor Rather than Cytosolic Immune Detection in Restricting Coxiella burnetii Phase II Replication within Mouse Macrophages. Infect Immun 84:998-1015
Kohler, Lara J; Roy, Craig R (2015) Biogenesis of the lysosome-derived vacuole containing Coxiella burnetii. Microbes Infect 17:766-71
Copenhaver, Alan M; Casson, Cierra N; Nguyen, Hieu T et al. (2014) Alveolar macrophages and neutrophils are the primary reservoirs for Legionella pneumophila and mediate cytosolic surveillance of type IV secretion. Infect Immun 82:4325-36
Choy, Augustine; Roy, Craig R (2013) Autophagy and bacterial infection: an evolving arms race. Trends Microbiol 21:451-6
Sherwood, Racquel Kim; Roy, Craig R (2013) A Rab-centric perspective of bacterial pathogen-occupied vacuoles. Cell Host Microbe 14:256-68
Case, Christopher L; Kohler, Lara J; Lima, Jonilson B et al. (2013) Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc Natl Acad Sci U S A 110:1851-6
Ivanov, Stanimir S; Roy, Craig R (2013) Pathogen signatures activate a ubiquitination pathway that modulates the function of the metabolic checkpoint kinase mTOR. Nat Immunol 14:1219-28
Roy, Craig R (2012) Vacuolar pathogens value membrane integrity. Proc Natl Acad Sci U S A 109:3197-8
Choy, Augustine; Dancourt, Julia; Mugo, Brian et al. (2012) The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338:1072-6

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