A hallmark of microbes is the ability to alter their physiology to tolerate or exploit local conditions. Adaptation is crucial for pathogens, since these microorganisms confront distinct environments as they cycle between periods of colonization and transmission. As an experimental model to elucidate the impact of microbial differentiation on pathogenesis, we analyze a gram-negative intracellular pathogen of phagocytes. Here we test the hypothesis that, to thrive in the human lung and its aquatic reservoir, L. pneumophila expresses in a reciprocal pattern at least two distinct sets of biochemical pathways: one to promote replication in phagocyte vacuoles and the other to stimulate transmission between host cells. The hypothesis that its LetA/S two- component regulatory system is designed to confer versatility to the pathogen will also be tested. By exploiting knowledge of the regulatory circuit that governs L. pneumophila differentiation, mutants that lack the regulators FliA, LetA, LetS, or CsrA, or the threonine tranporter PhtA, the genome sequences of the Philadelphia, Paris and Lens strains, bioinformatic and microarray technology, and molecular and genetic assays of function, mechanisms that equip pathogens to cycle between intracellular replication and transmission can be elucidated. The molecular features critical to each stage of the life cycle can inform design of agents to eradicate this opportunistic pathogen from contaminated water supplies and from the infected lung. Together, these studies will provide a framework to investigate the biochemical pathways that equip intracellular microbes to emerge from the environment to cause opportunistic infections. Thus, concepts and pathways identified here can also guide studies and management of less tractable intracellular pathogens such as the Mycobacteria, Chlamydia, Francisella, and Coxiella species.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI044212-09S1
Application #
7846541
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Korpela, Jukka K
Project Start
2009-06-05
Project End
2010-10-31
Budget Start
2009-06-05
Budget End
2010-10-31
Support Year
9
Fiscal Year
2009
Total Cost
$15,759
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Dalebroux, Zachary D; Svensson, Sarah L; Gaynor, Erin C et al. (2010) ppGpp conjures bacterial virulence. Microbiol Mol Biol Rev 74:171-99

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