Urinary tract infection is the most frequently diagnosed kidney and urologic disease and E. coli is by far the most common etiologic agent. Certain E. coli phenotypes such as P fimbriation and hemolysin production are found more frequently in strains isolated from the urine of patients with acute pyelonephritis and cystitis than in feces from normal individuals. Indeed, the expression of P fimbriae and hemolysin was long thought to explain the virulence of these strains in the urinary tract, yet mutation of these genes in our laboratory did not significantly diminish virulence in an experimental CBA mouse model of infection. Recently, defined blocks of DNA termed """"""""pathogenicity islands"""""""" have been found in uropathogenic strains to carry genes not generally found in fecal strains. We have characterized, by cloning and nucleotide sequencing, a 60-kb pathogenicity island on the chromosome of uropathogenic E. coli CFT073, isolated from the blood and urine of a woman with acute pyelonephritis. Evidence has been obtained for a second PAI. Secreted proteins have also emerged as key elements in models of pathogenesis and are produced by this and other urovirulent strains in our strain collection. It is also likely that genes common to all E. coli also play some role in the pathogenesis of cystitis and acute pyelonephritis. We hypothesize that genes within pathogenicity islands, secreted proteins, modulation of type 1 fimbriae all contribute directly to the development and pathogenesis of ascending urinary tract infection.
As specific aims, we propose: 1) To identify secreted proteins unique to uropathogenic strains of E. coli; 2) To evaluate putative virulence genes encoded by a pathogenicity island of uropathogenic E. coli CFT073; 3) To identify and characterize a second set of pathogenicity island sequences associated with uropathogenic E. coli CFT073; and 4) To determine the position (On-Off) of the fim invertible element that controls transcription of Type 1 fimbria genes during acute urinary tract infection caused by E. coli.
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