Rat Strains Differ in Susceptibility to Ureaplasma parvum -Induced Urinary Tract Infection and Struvite Stone Formation

Abstract

Individuals with struvite uroliths are susceptible to recurrent urinary tract infections (UTI), sepsis, and renal disease. Unfortunately, little is known about the host-specific factors that predispose to this disease. In order to develop a rodent model that can address this problem, we inoculated female Fischer 344 (F344), Lewis (LEW), Sprague-Dawley (SD), and Wistar (WIS) rats with a host-adapted strain of Ureaplasma parvum. Animals were necropsied at 2 weeks postinoculation; 100% of F344, 42% of SD, 10% of LEW, and 10% of WIS rats remained infected. Severe bladder lesions and struvite calculi were seen in 64% of F344 rats; in other rat strains, bladder lesions were mild or absent. F344 rats with struvite uroliths had the highest urinary levels of proinflammatory cytokines, such as GRO/KC, interleukin-1␣ (IL-1␣), and IL-1␤. F344 rats without struvite stones at necropsy had milder bladder lesions and significantly lower urinary levels of proinflammatory cytokines but a more prominent inflammatory response than did other rat strains. Based on our results, struvite stone formation is linked to a robust inflammatory response that does not resolve UTI but instead promotes damage to surrounding tissues.Although struvite calculi constitute only 2 to 3% of stones that are analyzed, they create greater clinical complications, such as sepsis and renal disease (30), than any other stone type. Not all factors that contribute to struvite stone formation are known, but urinary tract infections (UTI) are usually a predisposing factor. Infections with urease-producing bacteria, such as Klebsiella, Proteus, Pseudomonas, and Ureaplasma, significantly increase the risk of struvite formation due to increases in urine pH and direct damage of the uroepithelium by ammonia (13, 29).Host-specific factors also increase the risk of struvite formation during a UTI episode. Obvious examples of host-specific factors are anatomic anomalies of the urogenital tract that disrupt the capacity to void urine (13, 29). However, in most patients a predisposing factor cannot be identified, and the underlying cause of struvite stone formation remains unclear. Since UTI is a prerequisite for struvite stone formation, risk factors for UTI also need to be considered. In women, colonization of the vagina with potential uropathogens combined with impaired host defense mechanisms increases the risk of UTI (7,32,38). In addition, genetic factors have been postulated to play a role in susceptibility to UTI (37).Although ureaplasmas are not the only urease-producing bacteria known to cause struvite calculi (11,12,14), they are uniquely considered opportunistic pathogens because they can be readily isolated from the lower urogenital tract of healthy humans as well as individuals with disease (26, 39). Epidemiological studies show that women have much higher Ureaplasma colonization rates (5) as well as higher rates of infection-induced calculi that are culture positive for Ureaplasma (19) than do men. Since most diseases caused by mollicutes are influenced by a...

Complicated Urinary Tract Infection Is Associated with Uroepithelial Expression of Proinflammatory Protein S100A8

“…Tissues were cultured for the presence of U. parvum, and bladders were evaluated by histopathologic analyses. For proteome studies, animals infected for 2 weeks and the corresponding bladder tissues were assigned to the asymptomatic UTI or struvite group based on culture status, the urine cytokine profile, histology, and the presence of struvite uroliths (21). Animals within the UTI group were culture positive at the time of necropsy and had minimal histologic lesions, low urine cytokine levels, and no evidence of struvite uroliths.…”

“…All procedures were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee. Sterile 10B broth or a rat-adapted strain of U. parvum (21) was inoculated directly into the bladders of rats, and tissues were harvested at 1, 2, and 3 days and 2 weeks postinoculation (p.i.). Tissues were cultured for the presence of U. parvum, and bladders were evaluated by histopathologic analyses.…”

“…The genetically inbred Fischer (F344) rat is susceptible to UTI induced by the obligate urease producer Ureaplasma parvum (21). F344 rats experimentally inoculated with the same doses and strains of U. parvum develop two clinical profiles in response to infection: asymptomatic UTI and UTI complicated by chronic active inflammation and struvite stone formation.…”

Urothelial hyperplasia with calculi (papillomatosis) in the urinary bladder of a male spontaneous diabetic Torii rat

“…In this case, struvite was suggested as the main component of uroliths. Struvite is normally present in rat urine, and infec- tions with urease-producing bacteria are a significant predisposing factor to increase the risk of struvite formation due to higher urinary pH and urothelial damage by ammonia 6,12 . The causative factor (e.g., genetic, metabolic, and/ or uropathogenic) of the marked struvite stone formation in the SDT rat was unclear, although no apparent bacterial infection was pathologically indicated in the urinary tract.…”

The Role of Calgranulins in Urinary Tract Infection

“…Values in the graph represent the mean ± sd (n = 4) of 2 independent experiments. Chemokine and cytokine concentrations were measured with a multiplex antibody assay as previously described (Reyes, et al 2006). Ureaplasmal infections are asymptomatic as long as their colonization is restricted to the urogenital mucosa.…”