CONTRIBUTION OF PROTEUS-MIRABILIS UREASE TO PERSISTENCE, UROLITHIASIS, AND ACUTE PYELONEPHRITIS IN A MOUSE MODEL OF ASCENDING URINARY-TRACTINFECTION

Proteus mirabilis, a significant cause of bacteriuria and acute pyelon ephritis in humans, produces urease. This high-molecular-weight, multi meric, cytoplasmic enzyme hydrolyzes urea to ammonia and carbon dioxid e. To assess the role of urease in colonization, urolithiasis, and acu te pyelonephritis in an animal model of ascending urinary tract infect ion, we compared a uropathogenic strain of P. mirabilis with its isoge nic urease-negative mutant, containing an insertion mutation within ur eC, the gene encoding the large subunit of the enzyme. Mice challenged transurethrally with the parent strain developed significant bacteriu ria and urinary stones. The urease-negative mutant had a 50% infective dose of 2.7 x 10(9) CFU, a value more than 1,000-fold greater than th at of the parent strain (2.2 X 10(6) CFU). The urease-positive parent strain reached significantly higher concentrations and persisted signi ficantly longer in the bladder and kidney than did the mutant. Indeed, in the kidney, the parent strain increased in concentration while the mutant concentration fell so that, by 1 week, the parent strain conce ntration was 10(6) times that of the mutant. Similarly, the urease-pos itive parent produced significantly more severe renal pathology than t he mutant. The initial abnormalities were in and around the pelvis and consisted of acute inflammation and epithelial necrosis. By 1 week, p yelitis was more severe, crystals were seen in the pelvis, and acute p yelonephritis, with acute interstitial inflammation, tubular epithelia l cell necrosis, and in some cases abscesses, had developed. By 2 week s, more animals had renal abscesses and radial bands of fibrosis. We c onclude that the urease of P. mirabilis is a critical virulence determ inant for colonization, urolithiasis, and severe acute pyelonephritis.