Salmonellae are facultative intracellular pathogens that cause disease in humans and animals, including enteric (typhoid) fever and gastroenteritis. Typhoidal and non-typhoidal salmonellosis continues to cause significant morbidity and mortality worldwide. The overall objectives of this work are to better understand the induction of pathogenic bacterial gene expression in response to eukaryotic cell environments, as well as how bacteria utilize regulatory networks induced within these environments to avoid host innate immune killing. Antimicrobial peptides (AP), found at mucosal surfaces and within phagocytes, are a key weapon in the host innate immune arsenal. Two-component regulatory systems enable bacteria to sense their external environment and to mount an adaptive response by altering gene expression. Two such systems in Salmonella that are induced within the host during infection (PhoP-PhoQ; PmrA-PmrB) interact to remodel the outer membrane, including the lipopolysaccharide (LPS), which is the primary surface molecule that interacts with AP. We have recently identified a third member of this two-component cascade, UblA-UblB. PmrA-PmrB mediated modifications render the LPS less anionic, which leads to a reduced sensitivity to cationic AP, and these modifications have been shown to be necessary for oral virulence in mice. Further study of the in vivo induced PmrA-PmrB system and its role in LPS modification and virulence is necessary to better understand Salmonella pathogenesis and resistance to host innate immune killing.
The aims of this grant are: (1) Characterization of novel PmrA-PmrB-regulated genes, (2) The role of PmrA-PmrB-mediated LPS modification in Salmonella virulence, and (3) The interaction of the UblA-UblB and PmrA-PmrB two-component regulatory systems. Understanding these regulated mechanisms by which salmonellae survive within the animal host could lead to novel therapeutic, preventative and diagnostic strategies, and are likely to be applicable to the studies of other bacterial pathogens of humans. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI043521-07A1
Application #
6728901
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Alexander, William A
Project Start
1998-07-15
Project End
2008-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
7
Fiscal Year
2004
Total Cost
$299,000
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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