Copper is a Host Effector in Protection Against Urinary Tract Infection

泌尿道，特别是膀胱，是细菌感染的最常见部位之一， 人类尿路致病性大肠杆菌（UPEC）是引起尿路感染（UTI）的主要原因。 妇女、儿童、老年人和导尿管、尿石或糖尿病患者的尿失禁率很高， 对UTI敏感。目前迫切需要新的策略来管理UTI，因为令人担忧的是， 全球UPEC抗生素耐药性增加。我们已经证明，铜（Cu）被动员， 尿液作为患者临床UTI期间的宿主反应。我们开发了一种非人类灵长类动物模型， 在人UTI中观察到尿铜动员的UTI。我们的调查结果与报告一起 Menkes病患者（不能吸收饮食中的铜）的暴发性UTI，突出了一个重要的， 铜在预防UTI中的新生物学作用。我们的长期研究目标是确定 和UTI期间宿主-病原体相互作用的细胞特征，以鉴定治疗开发的靶点。 本提案的主要目的是确定铜介导的抗UPEC保护机制 定殖，并确定在UTI期间Cu如何被动员到尿中。根据我们发布的和 根据初步数据，我们假设Cu被动员到尿液中，以响应UPEC信号，从而阻碍 细菌存活，并且增加Cu的毒性将促进UPEC清除。的理由 拟议的工作是，了解铜的动员，及其对UPEC生存的影响是至关重要的， 开发治疗方法，支持这种先天反应，以解决UTI。我们将测试我们的中心假设， 追求以下具体目标：1）确定铜如何阻止UPEC存活，并鉴定病原体 触发铜动员的信号; 2）定义铜介导的UPEC杀伤机制， 人吞噬细胞;和3）确定增强铜的毒性对UPEC清除的影响。的 本研究的预期结果包括了解铜对UPEC的直接和间接影响 UTI期间的清除，以及触发Cu动员的病原体信号的识别。我们将 确定Cu介导的人吞噬细胞中UPEC杀伤的机制。提高铜含量的治疗方法是 预期在UTI的小鼠和非人灵长类动物模型中促进UPEC清除。大幅 这项研究的积极影响将是阐明先天宿主防御效应子在保护 人类的UTI这项拟议中的研究意义重大，因为我们的发现有望开辟新的领域。 开发新的抗UTI干预措施。我们的方法是创新的，因为我们寻求支持一个主机 它是一种易于饮食和药理学调节的效应物，以促进UTI的消退。总的来说， 这项拟议的研究预计将对UTI产生重大的公共卫生效益，UTI是一种普遍存在的， 影响数百万人的极度痛苦的传染病。

The urinary tract, especially the bladder, is one of the most common sites of bacterial infection in humans. Uropathogenic Escherichia coli (UPEC) is the predominant cause of urinary tract infection (UTI). Women, children, the elderly, and individuals with catheters, uroliths, or diabetes mellitus are highly susceptible to UTI. There is an immediate need for novel strategies to manage UTI because of an alarming increase in antibiotic resistance in UPEC globally. We have demonstrated that copper (Cu) is mobilized to urine as a host response during clinical UTI in patients. We have developed a non-human primate model of UTI that recapitulates urinary Cu mobilization observed in human UTI. Our findings, taken together with reports of fulminant UTI in patients with Menkes disease (who cannot absorb dietary Cu), highlight an important and novel biological role for Cu in the protection against UTI. Our long-term research goal is to define the molecular and cellular features of host-pathogen interaction during UTI to identify targets for therapeutic development. Major objectives of this proposal are to define the mechanism of Cu-mediated protection against UPEC colonization, and to determine how Cu is mobilized to urine during UTI. Based on our published and preliminary data, we hypothesize that Cu is mobilized to urine in response to UPEC signals to impede bacterial survival, and that augmenting the toxicity of Cu will promote UPEC clearance. The rationale for the proposed work is that understanding Cu mobilization, and its impact on UPEC survival are critical to develop therapeutics that bolster this innate response to resolve UTI. We will test our central hypothesis by pursuing the following specific aims: 1) Determine how copper deters UPEC survival, and identify pathogen signals that trigger copper mobilization; 2) Define the mechanism of copper-mediated UPEC killing within human phagocytes; and 3) Determine the effect of augmenting the toxicity of copper on UPEC clearance. The expected outcomes of this study include understanding the direct and indirect impact of Cu on UPEC clearance during UTI, and the identification of the pathogen signals that trigger Cu mobilization. We will determine the mechanism of Cu-mediated UPEC killing in human phagocytes. Cu-boosting treatments are anticipated to promote UPEC clearance in the mouse and non-human primate models of UTI. The substantial positive impact of this study will be elucidating the role of an innate host defense effector in protection against UTI in humans. The proposed research is significant because our findings are anticipated to break new ground to develop novel interventions against UTI. Our approach is innovative because we seek to bolster a host effector that is amenable to dietary and pharmacological modulation, to promote resolution of UTI. In summary, the proposed study is expected to confer a significant public health benefit against UTI, a ubiquitous and profoundly painful infectious disease affecting millions of people.