URINARY TRACT INFECTIONS--IMMUNE BASIS OF SUSCEPTIBILITY

尿路感染（UTI）仍然是一个常见的和严重的临床问题 影响了10-20%的女性 寻求治疗的妇女 急性UTI占超过500万人次的医生办公室 在美国，每年的医疗保健费用仅用于治疗不复杂的 下呼吸道感染每年花费近10亿美元。 最被接受的上行性UTI病理生理学假设是： 女性易感的是粪便中携带的泌尿道病原体植物群 依次定植于阴道口、尿道、膀胱，最后 肾脏 E.大肠杆菌菌株是大多数UTI的原因， 具有特异性的毒力因子，如对尿路上皮细胞的粘附 受体、某些O和K抗原以及溶血素。 的原因 女童和某些成年妇女的易感性增加， 未知，但可能是由于E.大肠杆菌转化为上皮细胞 阴道和膀胱内壁， 尿液中的抗感染抗体 可能增大 免疫抑制患者（移植后和艾滋病）中UTI的发生率。 免疫缺陷在UTI中的作用尚未得到认真研究。 免疫缺陷在尿路感染可能是一个关键的和迄今尚未确定的因素 来解释可解释性。 我们的工作与动物模型的上升E。大肠杆菌UTI在人类中 表明：1）严重的T和B细胞免疫缺陷增加 小鼠对诱导UTI的易感性; 2）T和B的免疫重建 细胞缺陷小鼠恢复对UTI的抗性; 3）猴的免疫 或小鼠杀死，全细胞疫苗减轻了诱导的严重性， 尿路感染。 这项研究旨在证明我们的假设，即先天性或 诱导的免疫缺陷是一个重要的诱发因素， 回归E. coli UTI。 我们将：1）确定先天性免疫缺陷， 增加对UTI易感性的小鼠; 2）鉴定免疫遗传性 增加患者对复发性UTI易感性的倾向;以及 3)确定E.大肠杆菌毒力因子调节 免疫缺陷小鼠中的UTI。

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.