Distinguishing pathogenic from non-pathogenic microbes presents an interesting challenge to the host immune system and is critical for eliciting the appropriate immune response to combat the invading pathogen. Vacuolar pathogens have evolved multiple strategies to manipulate host functions to promote intracellular survival, necessitating co-evolution of immune molecular sensory networks that detect the pathogen attempts at subversion. To dissect how this process occurs at the molecular level we have developed methodology that monitors modifications on host proteins to reverse-engineer the host response networks to pathogenic infection in silico. To this end, we are using the respiratory pathogen Legionella pneumophila as a model organism to decipher specific regulation of host cellular pathways to pathogenic challenge. The overall goal of the project is to use biochemical and molecular approaches to characterize how cellular pathways in macrophages utilize regulatory molecular modifications, such as ubiquitin, to specifically alter the outcome of signaling cascades in response pathogenic infection. Specific emphasis is placed on the cellular cascades that coordinate the cytokine response of innate immune cells.

Public Health Relevance

Deciphering the molecular interactions between the respiratory bacterial pathogen Legionella pneumophila and cells of the innate immune system will uncover how the host distinguishes virulent from avirulent microbes to initiate appropriate antimicrobial responses. This knowledge will ultimately aid in the design of more effective antimicrobial therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI097847-02
Application #
8415836
Study Section
Special Emphasis Panel (ZRG1-IDM-A (80))
Program Officer
Gondre-Lewis, Timothy A
Project Start
2012-02-01
Project End
2014-04-30
Budget Start
2013-02-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$207,865
Indirect Cost
$82,865
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520