EFFECT OF CRANBERRY CONSTITUENTS ON UTI PATHOGENESIS

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DESCRIPTION (provided by applicant): Urinary tract infections (UTIs) are among the most common bacterial infections, with symptoms that can include dysuria, urgency and frequency of urination, flank pain and fever. Clinical diagnosis is based on symptoms and the laboratory finding of bacteriuria. Women of all ages are especially susceptible to acute and recurrent infections. Because of the rise in antibiotic-resistant bacteria and the deleterious effects of long-term antibiotic prophylaxis, alternative therapies for UTIs are needed. Alternative therapies proposed for treatment of acute and recurrent UTIs have included the ingestion of cranberries or cranberry juice. The actions ascribed to cranberries include acidification of the urine, inhibition of kinases, and anti-inflammatory, anti-adhesive and anti-oxidant effects. The Vorsa laboratory has fractionated cranberry fruit into the major flavonoid classes of proanthocyanidins, flavonols and anthocyanins. Through bioassay directed fractionation, the cranberry proanthocyanidin fraction was shown to contain compounds that can inhibit the aggregation of human erythrocytes by bacteria expressing PapG, the bacterial adhesin associated with pyelonephritis. In addition, the flavonol extract exhibited high anti-inflammatory activity in a TPA-induced mouse ear edema model. The Hultgren laboratory has utilized a mouse model of cystitis to elucidate the structure, function and mechanism of action of bacterial and host factors involved in the establishment and persistence of UTIs. The steps of the pathogenic cascade that occurs upon introduction of uropathogenic E. coli (UPEC) into the urinary tract has been delineated. This cascade includes bacterial binding and invasion into bladder epithelial cells, intracellular growth, fluxing, reservoir formation and reemergence leading to recurrence. The host responds by mounting an immune response that includes the release of cytokines and infiltration of PMNs. In collaboration, the Vorsa and Hultgren laboratories will investigate the bioavailability of specific cranberry constituents and their effects on each of the steps of UPEC pathogenesis and the host response. We will utilize compound and protein HPLC and FPLC purification, affinity chromatography, mouse models, extensive in vitro and tissue culture models, high resolution EM, DNA microarrays, mass spectroscopy, X-ray crystallography and videomicroscopy. This work will lead to a molecular under standing of the bioactivities of defined cranberry constituents on UPEC pathogenesis and may lead to better treatments for UTIs.