Salmonella are facultative intracellular pathogens which cause significant diseases in humans and animals. These organisms cause 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. Non-typhoidal 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 application proposes to study a set of virulence genes, termed Salmonella translocated effectors, that are translocated across the phagosome membrane into the eucaryotic cell cytoplasm by a type III secretion system encoded on Salmonella pathogenicity island II will be studied. This application proposes to further define these proteins, and to study in molecular detail their role in bacterial virulence.

Public Health Relevance

Salmonellosis is the most common cause of bacterial diarrhea in the United States and typhoid fever remains an important global health problem for which antibiotic resistance is increasing. Studies of the molecular mechanisms of Salmonella virulence for humans and animals could lead to new vaccines and therapeutic strategies to prevent and treat Salmonellae infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048683-14
Application #
8620600
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Alexander, William A
Project Start
2001-01-15
Project End
2016-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$377,557
Indirect Cost
$127,557
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
LaRock, Doris L; Chaudhary, Anu; Miller, Samuel I (2015) Salmonellae interactions with host processes. Nat Rev Microbiol 13:191-205
Kolodziejek, Anna M; Miller, Samuel I (2015) Salmonella modulation of the phagosome membrane, role of SseJ. Cell Microbiol 17:333-41
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
LaRock, Doris L; Brzovic, Peter S; Levin, Itay et al. (2012) A Salmonella typhimurium-translocated glycerophospholipid:cholesterol acyltransferase promotes virulence by binding to the RhoA protein switch regions. J Biol Chem 287:29654-63
Mills, Erez; Pultz, Ingrid S; Kulasekara, Hemantha D et al. (2011) The bacterial second messenger c-di-GMP: mechanisms of signalling. Cell Microbiol 13:1122-9
Vinh, Dani B N; Ko, Dennis C; Rachubinski, Richard A et al. (2010) Expression of the Salmonella spp. virulence factor SifA in yeast alters Rho1 activity on peroxisomes. Mol Biol Cell 21:3567-77
Levin, Itay; Eakin, Catherine; Blanc, Marie-Pierre et al. (2010) Identification of an unconventional E3 binding surface on the UbcH5 ~ Ub conjugate recognized by a pathogenic bacterial E3 ligase. Proc Natl Acad Sci U S A 107:2848-53
Ohlson, Maikke B; Huang, Zhiwei; Alto, Neal M et al. (2008) Structure and function of Salmonella SifA indicate that its interactions with SKIP, SseJ, and RhoA family GTPases induce endosomal tubulation. Cell Host Microbe 4:434-46
Wasylnka, Julie A; Bakowski, Malina A; Szeto, Jason et al. (2008) Role for myosin II in regulating positioning of Salmonella-containing vacuoles and intracellular replication. Infect Immun 76:2722-35
Haraga, Andrea; Ohlson, Maikke B; Miller, Samuel I (2008) Salmonellae interplay with host cells. Nat Rev Microbiol 6:53-66

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