Copper is a Host Effector in Protection Against Urinary Tract Infection

尿路，尤其是膀胱，是细菌感染的最常见部位之一。 人类。尿路致病性大肠埃希菌(UPEC)是引起尿路感染(UTI)的主要原因。 妇女、儿童、老年人和有导尿管、尿结石或糖尿病的个人高度危险 易受尿路感染的。由于一个令人担忧的问题，迫切需要新的战略来管理UTI 全球UPEC的抗生素耐药性增加。我们已经证明了铜(Cu)被动员到 尿液作为宿主在临床尿路感染中的反应。我们已经开发了一种非人类灵长类动物模型 尿路感染，概括了在人类尿路感染中观察到的尿铜动员。我们的发现与报告结合在一起 在Menkes病患者(不能吸收膳食铜)中暴发性尿路感染的研究，强调了一个重要的和 铜在预防尿路感染中的新生物学作用。我们的长期研究目标是定义分子 以及UTI期间宿主-病原体相互作用的细胞特征，以确定治疗开发的靶点。 这项提议的主要目标是确定铜介导的保护UPEC的机制 定植，并确定尿路感染期间铜如何被动员到尿液中。基于我们发布的和 初步数据，我们假设铜被尿液动员，以响应UPEC信号来阻碍 细菌存活，增加铜的毒性将促进UPEC的清除。其基本原理是 拟议的工作是，了解铜动员及其对UPEC存活的影响对于 开发治疗方法来支持这种天生的反应来解决尿路感染。我们将通过以下方式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，并确定病原体 触发铜动员的信号；2)确定铜介导的UPEC杀伤机制 以及3)确定增加铜的毒性对UPEC清除的影响。这个 这项研究的预期结果包括了解铜对UPEC的直接和间接影响 尿路感染期间的清除，以及触发铜动员的病原体信号的识别。我们会 确定铜介导的UPEC对人吞噬细胞的杀伤机制。提高铜含量的治疗是 预计将促进UPEC在小鼠和非人类灵长类UTI模型中的清除。实质性的 这项研究的积极影响将是阐明先天宿主防御效应器在保护 人类的尿路感染。这项拟议的研究意义重大，因为我们的发现有望开辟新的天地。 开发针对尿路感染的新干预措施。我们的方法是创新的，因为我们寻求支持一位 对饮食和药物有调节作用的效应物，可促进尿路感染的解决。总而言之， 这项拟议的研究预计将赋予UTI显著的公共健康益处，UTI是一种普遍存在的 影响数百万人的极其痛苦的传染病。

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.