Mucosal Immune Defense Mechanisms of the Urinary Bladder

描述（由申请人提供）：粘膜表面必须允许将生命所需的代谢物交换到宿主中，排泄/排除宿主中的废物和毒素，同时保持对侵入性微生物的第一道防线。然而，为了对抗微生物感染而引起的粘膜炎症，如果不加以控制，也会破坏粘膜屏障的完整性。许多粘膜表面与微生物持续或短暂接触，但控制粘膜表面炎症反应程度的分子机制和保护性适应性粘膜反应的分子基础尚不清楚。本提案将通过组建一个经验丰富的研究团队来研究这些机制，他们具有不同和互补的专业知识，以研究膀胱抵抗细菌感染的粘膜免疫防御机制。我们将验证以下假设：在细菌感染的最初几个小时内，免疫信号通路的整合，包括来自膀胱上皮的免疫信号通路，构成了一个粘膜免疫检查点，对疾病的结果和膀胱粘膜重塑有深远的影响。本研究将利用一种简单且易处理的小鼠下尿路细菌感染模型，探索急性、慢性和复发性感染时膀胱黏膜的这些免疫防御途径。提出的实验方法将为粘膜免疫学领域提供重要的见解。这些研究将探讨特异性先天信号通路（Aim 1）和细胞反应（Aim 2）在幼年小鼠急性感染早期的作用，以及适应性变化（如慢性炎症细胞浸润和IgA产生）在建立对复发性感染的敏感性或保护作用（Aim 3）中的作用。这些研究将揭示粘膜对细菌防御机制的新细节，拓宽对粘膜炎症调节和粘膜上皮与免疫细胞之间信号传导的认识，从而促进我们对慢性和复发性感染的易感性和保护的认识。这些见解将有助于开发针对粘膜的新型疫苗和治疗方法。

DESCRIPTION (provided by applicant): Mucosal surfaces must allow the exchange of metabolites required for life into the host and excretion/exclusion of wastes and toxins out of the host, while also maintaining a first line of defense against invasive microbes. However, mucosal inflammation, elicited to combat microbial infection, can also damage the integrity of the mucosal barrier, if not controlled. Many mucosal surfaces are in constant or transient contact with microbes, yet the molecular mechanisms governing the extent of the inflammatory response at the mucosal surface and the molecular basis of a protective adaptive mucosal response are poorly understood. This proposal will investigate these mechanisms by assembling an experienced team of investigators with diverse and complimentary expertise to investigate the mucosal immune defense mechanisms of the urinary bladder against bacterial infection. We will test the hypothesis that the integration of immune signaling pathways within the first few hours of bacterial infection, including those from the bladder epithelium, constitute a mucosal immune checkpoint that has a profound impact upon the outcome of disease and bladder mucosal remodeling. The proposed research will utilize a simple and highly tractable murine model of lower urinary tract bacterial infection to probe these immune defense pathways of the bladder mucosa during acute, chronic and recurrent infection. The experimental approaches proposed will provide critical insights in the field of mucosal immunology. These studies will investigate the role of specific innate signaling pathways (Aim 1) and cellular responses (Aim 2) early in acute infection of naive mice, and the role of adaptive changes such as chronic inflammatory cell infiltrates and IgA production in establishing sensitivity to or protection from recurrent infection (Aim 3). These investigations will reveal new details of the mechanisms of mucosal defense against bacteria, broadening the understanding of the regulation of mucosal inflammation and the signaling between mucosal epithelia and immune cells, and thus advance our understanding of chronic and recurrent infection susceptibility and protection. These insights will contribute to the development of novel vaccines and therapeutics targeting the mucosa. PUBLIC HEALTH RELEVANCE: These experiments are designed to reveal new mechanisms of mucosal defense against bacteria. Such findings would advance our understanding of both protective and damaging inflammatory responses at the mucosa, potentially contributing to the design of vaccines and raising new avenues for therapeutic intervention in chronic inflammatory conditions of the mucosa.