Strains of uropathogenic Escherichia coli (UPEC) are the principal causative agents of urinary tract infections (UTIs), which continuously rank among the most common of infectious diseases. UPEC can 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 chronic and recurrent acute UTIs. Mounting evidence indicates that UPEC entry into host cells and tissues within the urinary tract promotes bacterial persistence in the face of both innate and adaptive host defenses, as well as antibiotic treatments. Virtually all UPEC isolates encode filamentous adhesive organelles called type 1 pili. We have found that the type 1 pilus adhesin FimH can engage host 1321 integrin receptors in a non-canonical fashion and thereby activate signaling cascades that result in the actin-dependent internalization of UPEC. Our preliminary data indicate that FimH-mediated bacterial invasion of host cells is dependent upon crosstalk between the actin and microtubule cytoskeletal networks, although the nature of this crosstalk remains undefined. The entry process also requires input from clathrin and distinct clathrin-associated adaptor proteins. Clathrin is best characterized for its role in the uptake of small molecules such as growth factors, but its ability to promote internalization of much larger particles like UPEC and other invasive pathogens has only recently been appreciated and remains poorly understood. The primary objectives of this application are to define the host factors that mediate UPEC invasion of bladder epithelial cells, with a focus on the functional roles of microtubule-actin crosstalk and clathrin. The impact that host cell invasion has on the establishment and persistence of UPEC within the host will also be assessed. It is hoped that the proposed work will provide a more complete understanding of the pathogenesis of acute, recurrent, and chronic UTIs, ultimately facilitating the development of improved therapeutics for treating and preventing these exceptionally common infections.
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.
|Barber, Amelia E; Mulvey, Matthew A (2014) Reply to Kaye and Sobel. Clin Infect Dis 58:444-5|
|Blango, Matthew G; Ott, Elizabeth M; Erman, Andreja et al. (2014) Forced resurgence and targeting of intracellular uropathogenic Escherichia coli reservoirs. PLoS One 9:e93327|
|Wiles, Travis J; Norton, J Paul; Russell, Colin W et al. (2013) Combining quantitative genetic footprinting and trait enrichment analysis to identify fitness determinants of a bacterial pathogen. PLoS Genet 9:e1003716|
|Debnath, Irina; Norton, J Paul; Barber, Amelia E et al. (2013) The Cpx stress response system potentiates the fitness and virulence of uropathogenic Escherichia coli. Infect Immun 81:1450-9|
|Barber, Amelia E; Norton, J Paul; Spivak, Adam M et al. (2013) Urinary tract infections: current and emerging management strategies. Clin Infect Dis 57:719-24|
|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|
|Wiles, Travis J; Mulvey, Matthew A (2013) The RTX pore-forming toxin ýý-hemolysin of uropathogenic Escherichia coli: progress and perspectives. Future Microbiol 8:73-84|
|Donovan, Grant T; Norton, J Paul; Bower, Jean M et al. (2013) Adenylate cyclase and the cyclic AMP receptor protein modulate stress resistance and virulence capacity of uropathogenic Escherichia coli. Infect Immun 81:249-58|
|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|