Urinary tract infections (UTI) remain a common clinical problem. They have especially high morbidity in children and may lead to severe pyelonephritis and bacteremia. Most UTIs have an ascending route from the E. coli in fecal and introital flora. Depending on the type of surface proteins (fimbriae) on the E. coli, the infection may be limited to cystitis; whereas other E. coli strains (P-fimbriated) are likely to cause pyelonephritis. Following certain types of human and experimental UTI, there is an increase in locally secreted immunoglobulins, especially secretory IgA. This immune response can be augmented by immunization. Our previous research in rats has presented evidence that immunization against UTI is best achieved by instillation of antigens onto a contiguous mucosal surface, the vagina. Vaginal immunization against UTI induces an IgA and IgG immune response in the bladder as measured by an ELISA assay, causes decreased bacterial adherence to bladder epithelium, results in faster resolution of an induced UTI, and decreases damage to the bladder epithelium as visualize by scanning electron microscopy. In this proposal, we plan to extend this vaginal immunizing program to assess whether we can protect cynomolgus monkeys against induced ascending UTI. Following induction of cystitis or pyelonephritis with E. coli strains (including some with P-fimbriae), immunized monkeys will be compared to non-immunized controls with regard to urinary bacterial counts, duration of bacteriuria, elevations of C-reactive protein, local secretion of antibodies, urinary and vaginal mucin levels, and other measures to assess the severity of the infection. In this way, we hope to define the optimal regimen to follow for vaginal immunization against UTIs in primates with the eventual goal of having an effective and safe immunizing regimen against UTIs in humans.
