URINARY TRACT INFECTIONS: IMMUNE BASIS OF SUSCEPTIBILITY

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Urinary tract infections (UTI) remain a common and serious clinical problem that affect 10-20% of all women in their lifetime. Women seeking treatment for acute UTI account for over 5 million visits to physicians' offices annually in the United States Health Care costs to treat only uncomplicated lower tract infections are nearly one billion dollars per year. The most-accepted hypothesis for the pathophysiology of ascending UTI in susceptible women is that uropathogens carried in the fecal flora sequentially colonize the vaginal introitus, urethra, bladder, and finally the kidneys. E. coli strains are responsible for the majority of UTIs and have specific virulence factors such as adhesions for uroepithelial cell receptors, certain O and K antigens, and hemolysins. The reasons for increased susceptibility of female children and certain adult women are unknown but may be due to increased binding of E. coli to epithelial cells lining the vagina and bladder in conjunction with decreased levels of urinary antibody to infecting organisms. There is also an increased incidence of UTIs in immunosuppressed patients (post-transplant and AIDS). The roles of immune defects in UTI have not been seriously studied. Immunodeficiencies in UTI may be a critical and heretofore undefined factor in explaining susceptibilities. Our work with animal models of ascending E. coli UTI in humans has demonstrated that: 1) severe T and B cell immune deficiency increases susceptibility to induced UTI in mice; 2) immune reconstitution of T and B cell-deficient mice restores resistance to UTI; 3) immunization of monkeys or mice with killed, whole-cell vaccines lessens the severity of an induced UTI. This research proposes to document our hypothesis that congenital or induced immunodeficiencies are an important predisposing factor in recurrent E. coli UTI. We will: 1) identify congenital immune deficits in mice that increase susceptibility to UTI; 2) identify immunogenetic predispositions that enhance patients' susceptibility to recurrent UTI; and 3) determine whether E. coli virulence factors modulate the pathogenesis of UTI in immunodeficient mice.