Salmonella are facultative intracellular pathogens which cause significant diseases in humans and animals. These organisms are responsible for several disease syndromes, including enteric (typhoid) fever, gastroenteritis, bacteremias and focal infections. Typhoid fever is a severe systemic illness which is mostly a problem in the developing world and in travelers. Nontyphoidal salmonella infections are increasing in the USA and are largely associated with contaminated food. Salmonellae infections are most severe in infants, the elderly, and in immunosuppressed individuals. This grant proposes to study the mechanism by which Salmonellae survive host innate immune killing. Innate immune killing involves the non-antigen specific mechanisms by which animals eliminate invading bacteria. Included in innate immune mechanisms are antimicrobial peptides produced at mucosal surfaces and within phagocytic cell granules and cytokines produced in response to recognition of bacterial lipid A. Pathogens such as Salmonellae have mechanisms to resist these killing mechanisms that are environmentally regulated. The genes encoding these mechanisms are the subject of this grant. They include the virulence regulators PhoP/PhoQ that respond to signals within host tissues and induce genes necessary for resistance to innate immune killing. These regulators are essential for human and animal virulence. PhoP/PhoQ regulate genes involved in surface remodeling of bacteria. These genes include those responsible for modification of the lipid and protein components of the outer membrane. This grant proposes to define the mechanism by which the PhoQ sensor histidine kinase is activated in response to environmental signals. This grant will also study the mechanisms by which the PhoP/Q regulated remodeling of membrane lipids occurs and its role in bacterial virulence and the structure.
The specific aims of this proposal are to define the structure and function of PhoQ, the genes and proteins involved in membrane remodeling, microbial virulence and resistance to cationic antimicrobial peptides.

Public Health Relevance

This grant will research how salmonellae survive attack from the host's immune system, which will contribute to an improved understanding of, and treatments for, salmoneallae-induced illnesses. Salmonella organisms are responsible for several disease syndromes, including enteric (typhoid) fever, gastroenteritis, bacteremias and focal infections. Salmonellae infections are most severe in infants, the elderly, and in immunosuppressed individuals. Currently Salmonellae are the number one cause of bacterial diarrhea in the United States.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030479-23
Application #
8316128
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
1991-02-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
23
Fiscal Year
2012
Total Cost
$377,979
Indirect Cost
$127,979
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Matamouros, Susana; Hager, Kyle R; Miller, Samuel I (2015) HAMP Domain Rotation and Tilting Movements Associated with Signal Transduction in the PhoQ Sensor Kinase. MBio 6:e00616-15
LaRock, Doris L; Chaudhary, Anu; Miller, Samuel I (2015) Salmonellae interactions with host processes. Nat Rev Microbiol 13:191-205
Dalebroux, Zachary D; Edrozo, Mauna B; Pfuetzner, Richard A et al. (2015) Delivery of cardiolipins to the Salmonella outer membrane is necessary for survival within host tissues and virulence. Cell Host Microbe 17:441-51
Hicks, Kevin G; Delbecq, Scott P; Sancho-Vaello, Enea et al. (2015) Acidic pH and divalent cation sensing by PhoQ are dispensable for systemic salmonellae virulence. Elife 4:e06792
Matamouros, Susana; Miller, Samuel I (2015) S. Typhimurium strategies to resist killing by cationic antimicrobial peptides. Biochim Biophys Acta 1848:3021-5
Thaipisuttikul, Iyarit; Hittle, Lauren E; Chandra, Ramesh et al. (2014) A divergent Pseudomonas aeruginosa palmitoyltransferase essential for cystic fibrosis-specific lipid A. Mol Microbiol 91:158-74
Dalebroux, Zachary D; Miller, Samuel I (2014) Salmonellae PhoPQ regulation of the outer membrane to resist innate immunity. Curr Opin Microbiol 17:106-13
Dalebroux, Zachary D; Matamouros, Susana; Whittington, Dale et al. (2014) PhoPQ regulates acidic glycerophospholipid content of the Salmonella Typhimurium outer membrane. Proc Natl Acad Sci U S A 111:1963-8
Hajjar, Adeline M; Ernst, Robert K; Fortuno 3rd, Edgardo S et al. (2012) Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica. PLoS Pathog 8:e1002963
Pultz, Ingrid Swanson; Christen, Matthias; Kulasekara, Hemantha Don et al. (2012) The response threshold of Salmonella PilZ domain proteins is determined by their binding affinities for c-di-GMP. Mol Microbiol 86:1424-40

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