Urinary tract infection (UTI) is the most frequently diagnosed kidney and urologic disease and Escherichia coli is by far its most common etiologic agent. Individuals at high risk include neonates, preschool girls, sexually active women, and elderly women and men. Half of all women experience at least one UTI, leading to 6.8 million annual physician visits, 1.3 million emergency room visits, and 245,000 hospitalizations with annual costs of $2.4 billion. Emergence of antibiotic resistance, allergic reaction to pharmaceuticals, alteration of normal gut flora, and failure to prevent recurrent infections document the need for effective prevention. Vaccination has been approached by several groups without marked or long lasting protection. Here, we present a plan to systematically identify surface-exposed proteins that are synthesized in vivo and are specific to uropathogenic strains of E. coli. Surface-exposed proteins will be determined by: screening for outer membrane proteins that react with sera from chronically infected mice;predicting surface-expressed proteins bioinformatically;and releasing surface-expressed domains by limited proteolysis. Candidate antigens that meet these sequential screens will be used for vaccination in the established murine model of urinary tract infection.
As Specific Aims, we propose to: 1) Identify surface- exposed proteins that are synthesized in vivo and conserved among uropathogenic E. coli strains;and 2) Determine the efficacy of candidate proteins as components of a multivalent subunit vaccine to protect against urinary tract infection. Our goal will be to include the most protective antigens in a multivalent subunit vaccine for prevention of UTI by uropathogenic E. coli.

Public Health Relevance

Urinary tract infection (UTI) is the most frequently diagnosed kidney and urologic disease and Escherichia coli is by far its most common etiologic agent. Individuals at high risk include neonates, preschool girls, sexually active women, and elderly women and men. Half of all women experience at least one UTI, leading to 6.8 million annual physician visits, 1.3 million emergency room visits, and 245,000 hospitalizations with annual costs of $2.4 billion. Emergence of antibiotic resistance, allergic reaction to pharmaceuticals, alteration of normal gut flora, and failure to prevent recurrent infections document the need for effective prevention. Vaccination has been approached by several groups without marked or long lasting protection. Here, we present a plan to systematically identify surface-exposed proteins that are synthesized in vivo and are specific to uropathogenic strains of E. coli for use in a vaccine to prevent urinary tract infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043363-13
Application #
7792487
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Korpela, Jukka K
Project Start
1998-09-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
13
Fiscal Year
2010
Total Cost
$338,397
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
Subashchandrabose, Sargurunathan; Mobley, Harry L T (2015) Back to the metal age: battle for metals at the host-pathogen interface during urinary tract infection. Metallomics 7:935-42
Alteri, Christopher J; Himpsl, Stephanie D; Mobley, Harry L T (2015) Preferential use of central metabolism in vivo reveals a nutritional basis for polymicrobial infection. PLoS Pathog 11:e1004601
Subashchandrabose, Sargurunathan; Mobley, Harry L T (2015) Virulence and Fitness Determinants of Uropathogenic Escherichia coli. Microbiol Spectr 3:
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Nesta, Barbara; Valeri, Maria; Spagnuolo, Angela et al. (2014) SslE elicits functional antibodies that impair in vitro mucinase activity and in vivo colonization by both intestinal and extraintestinal Escherichia coli strains. PLoS Pathog 10:e1004124
Subashchandrabose, Sargurunathan; Hazen, Tracy H; Rasko, David A et al. (2013) Draft genome sequences of five recent human uropathogenic Escherichia coli isolates. Pathog Dis 69:66-70
Alteri, Christopher J; Himpsl, Stephanie D; Pickens, Shannon R et al. (2013) Multicellular bacteria deploy the type VI secretion system to preemptively strike neighboring cells. PLoS Pathog 9:e1003608
Wiles, Travis J; Norton, J Paul; Smith, Sara N et al. (2013) A phyletically rare gene promotes the niche-specific fitness of an E. coli pathogen during bacteremia. PLoS Pathog 9:e1003175
Armbruster, Chelsie E; Mobley, Harry L T (2012) Merging mythology and morphology: the multifaceted lifestyle of Proteus mirabilis. Nat Rev Microbiol 10:743-54
Alteri, Christopher J; Mobley, Harry L T (2012) Escherichia coli physiology and metabolism dictates adaptation to diverse host microenvironments. Curr Opin Microbiol 15:3-9

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