EXCEEDTHE SPACEPROVIDED. Escherichia coE is the most common cause of community acquired urinary tract infection (UTI) and a leading cause of nosocomial UTIs and sepsis. There are an estimated 8 million physician visits per year in the U.S for UTIs with significant associated morbidity and expense (> $1,000,000,000). We tested the hypothesis that virulence genes responsible for the pathogenesis of fife-threatening E. coli extraintestinal infections, such as pyelonephritis and sepsis can be identified by comparison of the genome sequence of urosepsis E. coli strain CFT073 to either E. coli laboratory strain MG1655 or O157:H7 strain EDL933. We identified >300 CFT073-specific loci. The continued study of the region surrounding the D-serine deaminase genes (dsdCXA) is especially compelling. An allelic knockout mutant of dsdA which encodes D-serine deaminase, is unaltered in expression of type 1 pili-mediated adherence, but 300-fold more competitive than the wild type strain in colonizing the bladder or kidney of mice infected in an ascending model of UTI. DsdC is a positive effector of dsdXA transcription and a member of the lysR-family of regulators. By in vivo and in vitro gene expression techniques we will test the hypotheses that D-serine through interaction with either dsdC or other co-effectors affects expression of multiple genes that directly influence CFT073 pathogenesis in murine models of disease. We will also identify environmental conditions and additional genes that affect the expression of the dsdCXA genes. Two such gene candidates are ipuAB (integrase-like t2roteins of _uropathogens) that are immediately adjacent to the dsdCXA genes in the chromosome of CFT073 as well as other uropathogenic E. coll. ipuAB are homologs of the type 1 pili phase-switch recombinases,fimB andfimE that are linked to and control expression of the E. coli type 1 pilusfim operon. We will test the hypothesis that these genes provide an additional phase-switch system that controls expression of dsdCXA or other unknown genes. The objective of the proposed project is to identify and characterize critical virulence genes for E. coli involved in serious human diseases. This information will be of use for the development of new chemotherapeutic and vaccine strategies. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063250-03
Application #
6827362
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Mullins, Christopher V
Project Start
2002-12-13
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
3
Fiscal Year
2005
Total Cost
$339,543
Indirect Cost
Name
University of Wisconsin Madison
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Welch, Rodney A (2016) Uropathogenic Escherichia coli-Associated Exotoxins. Microbiol Spectr 4:
Hryckowian, Andrew J; Baisa, Gary A; Schwartz, Kevin J et al. (2015) dsdA Does Not Affect Colonization of the Murine Urinary Tract by Escherichia coli CFT073. PLoS One 10:e0138121
Hryckowian, Andrew J; Battesti, Aurelia; Lemke, Justin J et al. (2014) IraL is an RssB anti-adaptor that stabilizes RpoS during logarithmic phase growth in Escherichia coli and Shigella. MBio 5:e01043-14
Baisa, Gary; Stabo, Nicholas J; Welch, Rodney A (2013) Characterization of Escherichia coli D-cycloserine transport and resistant mutants. J Bacteriol 195:1389-99
Hryckowian, Andrew J; Welch, Rodney A (2013) RpoS contributes to phagocyte oxidase-mediated stress resistance during urinary tract infection by Escherichia coli CFT073. MBio 4:e00023-13
Raterman, Erica L; Shapiro, Daniel D; Stevens, Daniel J et al. (2013) Genetic analysis of the role of yfiR in the ability of Escherichia coli CFT073 to control cellular cyclic dimeric GMP levels and to persist in the urinary tract. Infect Immun 81:3089-98
Raterman, Erica L; Welch, Rodney A (2013) Chemoreceptors of Escherichia coli CFT073 play redundant roles in chemotaxis toward urine. PLoS One 8:e54133
Battaglioli, E J; Baisa, G A; Weeks, A E et al. (2011) Isolation of generalized transducing bacteriophages for uropathogenic strains of Escherichia coli. Appl Environ Microbiol 77:6630-5
Suhs, Kaleigh A; Marthaler, Brodie R; Welch, Rodney A et al. (2011) Lack of association between the Tlr4 (Lpsd/Lpsd) genotype and increased susceptibility to Escherichia coli bladder infections in female C3H/HeJ mice. MBio 2:e00094-11

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