URINARY TRACT INFECTIONS--IMMUNE BASIS OF SUSCEPTIBILITY

描述(改编自申请者摘要)：尿路 据估计，感染(UTI)发生在所有女性中的高达50% 一生一世。每年约有700万妇女患上急性胰腺炎 据估计，感染在医疗保健中占10亿美元 成本。10%-15%的成年女性会发生反复感染，需要 持续的医疗护理和抗生素的使用 预防性的。此外，下呼吸道感染可以上升到 肾脏，可能导致肾脏损伤或菌血症。寄主抗性 TO UTI由几种不同的机制组成，包括先天 免疫、炎症反应和适应性免疫反应。细胞因子， 吞噬细胞、自然杀伤细胞和T细胞在宿主防御中是活跃的 感染。我们的初步结果表明，功能缺陷 这些成分中的任何一种都会导致感染严重程度的增加 实验动物的膀胱和肾脏。也有证据表明 先天的和早期的细胞防御可以预防膀胱感染 从上升到肾脏。初步的遗传学研究表明 宿主对UTI易感性的增加有一个可遗传的成分。 因此，总体目标是更清楚地定义主机 在尿路感染期间活跃的反应，并识别 增加敏感度。具体目标是：1)确定 在UTI期间处于活动状态的细胞宿主防御机制 尤其是那些对预防下尿路最重要的 从肾脏上升到感染；2)评估假设 尿路感染易感人群抗体介导的对大肠杆菌抗原的低反应性 女性与T细胞调节或抗体诱导有关 回答；3)评估可遗传性状增加的假设 部分妇女反复尿路感染易感性的家族性分析 遗传模式；4)评估这样的假设：一个遗传位点(或 基因座)会增加对诱导性尿路感染的易感性。

DESCRIPTION (Adapted from the Applicant's Abstract): Urinary tract infections (UTI) are estimated to occur in up to 50% of all women in their lifetimes. Approximately seven million women per year develop acute infections that account for an estimated one billion dollars in health care costs. Recurrent infections develop in 10-15% of adult women and require ongoing medical care and use of antibiotics both acutely and prophylactically. In addition, lower tract infections can ascend to the kidneys, possibly leading to kidney damage or bacteremia. Host resistance to UTI's is comprised of several different mechanisms that include innate immunity, inflammatory responses, and adaptive immune responses. Cytokines, phagocytes, natural killer cells, and T cells are active in host defense to infections. Our preliminary results have shown that functional deficiencies in any of these components leads to increased severity of infections in the bladder and kidneys of experimental animals. There is also evidence that innate and early cellular defenses can act to prevent bladder infections from ascending to the kidneys. Preliminary genetic studies have indicated that increased host susceptibility to UTI's has a heritable component. Therefore, the overall objective is to more clearly define the host responses that are active during a UTI and to identify genetic factors that increase susceptibility. The specific aims are: 1) to identify the role of cellular host defense mechanisms that are active during a UTI and, in particular those that are most important in preventing lower tract infections from ascending to the kidneys; 2) to evaluate the hypothesis that antibody-mediated hyporesponsiveness to E. coli antigens in UTI-susceptible women is associated with T cell regulation or induction of antibody responses; 3) to evaluate the hypothesis that a heritable trait increases the susceptibility to some women to recurrent UTIs by analysis of familial inheritance patterns; 4) to evaluate the hypothesis that a genetic locus (or loci) in mice will increase susceptibilityto an induced UTI.