Strains of uropathogenic Escherichia coli (UPEC) are the primary causative agents of urinary tract infections (UTIs). UPEC isolates are able to transiently invade, survive and multiply within host cells and tissues within the urinary tract. This is potentially critical to the ability of UPEC to effectively colonize the urinary tract and may promote the establishment of long-term, low-level infections within the bladder. Such sub-clinical infections may serve as a source for the recurrent acute UTIs that plague many individuals throughout their lives. The primary objectives of this proposal are to define the mechanisms by which UPEC is able to move into the bladder epithelium, persist, multiply and eventually reemerge. Using cell culture and mouse UTI model systems, the host receptors and signaling pathway utilized by UPEC for entry into bladder epithelial cells will be defined. The capacity of the host actin cytoskeleton to modulate UPEC replication and reemergence will be determined. In addition, the ability of UPEC to highjack the host cell vesicular trafficking and sorting machinery will be assessed. This research will provide a greater understanding of UTIs, which presently rank among the most common of bacterial infections, and will contribute to the development of more efficacious antibacterial therapeutics. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK068585-01
Application #
6813727
Study Section
Special Emphasis Panel (ZRG1-UKGD (01))
Program Officer
Mullins, Christopher V
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$316,193
Indirect Cost
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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
Wiles, Travis J; Bower, Jean M; Redd, Michael J et al. (2009) Use of zebrafish to probe the divergent virulence potentials and toxin requirements of extraintestinal pathogenic Escherichia coli. PLoS Pathog 5:e1000697
Kulkarni, Ritwij; Dhakal, Bijaya K; Slechta, E Susan et al. (2009) Roles of putative type II secretion and type IV pilus systems in the virulence of uropathogenic Escherichia coli. PLoS One 4:e4752
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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