The urinary tract is normally a sterile environment, kept free of microbes by the flow of urine and by myriad anti-microbial molecules and effector immune cells. However, despite these formidable host defenses and the increasing usage of antibiotics, urinary tract infections (UTIs) remain among the most common of infectious diseases worldwide. Strains of uropathogenic Escherichia coli (UPEC), which are the principal cause of UTIs, are able to invade host bladder epithelial cells and subsequently multiply, forming large intracellular inclusions that resemble biofilms. Alternately, intracellular UPEC can persist at low levels in a more quiescent, non-replicating state that may serve as a reservoir for future recurrent acute infections. Invasion of host cells and tissues within the urinary tract promotes the persistence of UPEC in the face of both innate and adaptive host responses, as well as many antibiotic treatments. The primary objectives of this proposal are to define the host and bacterial factors that mediate UPEC invasion, intracellular growth, and persistence within the bladder epithelium. Biochemical, pharmacological, genetic, and microscopic approaches coupled with in vivo model systems will be employed. It is hoped that the proposed work will provide a more complete understanding of the pathogenesis of both acute and recurrent UTIs and ultimately facilitate the development of improved therapeutics for treating and preventing these exceptionally common infections.

Public Health Relevance

Urinary tract infections are among the most common of infectious diseases, representing a serious economic and medical burden worldwide. By delineating how uropathogenic bacteria colonize and persist within the host, we hope to facilitate the development of improved therapeutics.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Mullins, Christopher V
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Erman, Andreja; Lakota, Katja; Mrak-Poljsak, Katjusa et al. (2012) Uropathogenic Escherichia coli induces serum amyloid a in mice following urinary tract and systemic inoculation. PLoS One 7:e32933
Dhakal, Bijaya K; Mulvey, Matthew A (2012) The UPEC pore-forming toxin ýý-hemolysin triggers proteolysis of host proteins to disrupt cell adhesion, inflammatory, and survival pathways. Cell Host Microbe 11:58-69
Blango, Matthew G; Mulvey, Matthew A (2010) Persistence of uropathogenic Escherichia coli in the face of multiple antibiotics. Antimicrob Agents Chemother 54:1855-63
Dhakal, Bijaya K; Mulvey, Matthew A (2009) Uropathogenic Escherichia coli invades host cells via an HDAC6-modulated microtubule-dependent pathway. J Biol Chem 284:446-54
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Blango, Matthew G; Mulvey, Matthew A (2009) Bacterial landlines: contact-dependent signaling in bacterial populations. Curr Opin Microbiol 12:177-81
Bower, Jean M; Gordon-Raagas, Hannah B; Mulvey, Matthew A (2009) Conditioning of uropathogenic Escherichia coli for enhanced colonization of host. Infect Immun 77:2104-12
Wiles, Travis J; Kulesus, Richard R; Mulvey, Matthew A (2008) Origins and virulence mechanisms of uropathogenic Escherichia coli. Exp Mol Pathol 85:11-9
Dhakal, B K; Kulesus, R R; Mulvey, M A (2008) Mechanisms and consequences of bladder cell invasion by uropathogenic Escherichia coli. Eur J Clin Invest 38 Suppl 2:2-11

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