Mechanisms of IL-17 Mediated Host Defense in the Kidney

IL-17 介导的肾脏宿主防御机制

基本信息

批准号：
9144776
负责人：
Partha Sarathi Biswas
金额：
$ 30.67万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-20 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144776
关键词：
Abdomen Acute Adult Agonist Angiotensin-Converting Enzyme Inhibitors Animal Model Antifungal Agents Applications Grants Biochemical Blood Pressure Bradykinin Bradykinin Receptor Candida Candida albicans Candidiasis Catheterization Cells Cessation of life Chromatin Chronic Cleaved cell Clinical Clinical Trials Data Diagnosis Disease Disseminated candidiasis Distal Drug Targeting Drug resistance Epithelial Cells Equilibrium Experimental Models FDA approved Fatality rate Fibrosis Gene Expression Gene Targeting Goals Health Hematopoietic Stem Cell Transplantation Host Defense Host Defense Mechanism Human Hyphae Immune system Immunity Indwelling Catheter Infection Inflammation Injury Interleukin-17 Intervention Invaded Kallikrein-Kinin System Kidney Kidney Diseases Kidney Failure Kininogenase Kininogens Knowledge Life Link Liver Malignant Neoplasms Mediating Mediator of activation protein Modality Morbidity - disease rate Mouse Strains Mucous Membrane Mus Nosocomial Infections Operative Surgical Procedures Oral cavity Organ Oxidation-Reduction Pathogenesis Pathology Pathway interactions Patients Premature Birth RNA Interference Regulation Renal function Reporting Research Resistance Role Series Serine Protease Signal Pathway Signal Transduction Solid Sterility System Systemic disease Therapeutic Therapeutic immunosuppression Tissues Treatment Efficacy Tubular formation Urinary Kallikrein Vaccines candidemia cell type combat cytokine effective therapy fungus in vivo inhibitor/antagonist insight kidney cell mortality mouse model neonate new therapeutic target novel therapeutics overexpression pre-clinical preclinical study prophylactic receptor response vaccine development

项目摘要

DESCRIPTION (provided by applicant): Candida albicans is a commensal fungus that resides in the oral cavity and gut mucosa. Normally, healthy humans efficiently control the colonization of Candida. However, in certain conditions such as solid organ and hematopoietic stem cell transplantation, receipt of immunosuppressive therapy, cancer, premature birth or indwelling catheterization, Candida albicans can disseminate and cause life-threatening systemic disease. In fact, disseminated candidiasis is the 4th most common nosocomial infection, with fatality rates up to 40-60%. The lack of effective vaccines and development of drug resistance act as major constraints in successfully treating these patients. Therefore, there is a serious unmet clinical need to develop better therapeutic and prophylactic strategies to combat these fatal infections. During disseminated infection, Candida hyphae invade target organs, particularly kidney and liver. Death from candidemia results from renal insufficiency in a substantial number of patients. While the contribution of mucosal immune system in anti-Candida host defense has been well studied in recent years, the role of local immunity in target organs, particularly the kidney, is largely overlooked. The cytokine IL-17 has emerged as a key mediator of host defense against Candida species. Both humans and experimental mouse models deficient in IL-17 pathways such as the IL-17 receptor A (IL-17RA) are susceptible to disseminated candidiasis. Our preliminary data show that IL-17RA signaling in non-hematopoietic cells is required for renal defense against systemic Candida infection. Nevertheless, the underlying mechanisms of IL-17-mediated host defense against systemic candidiasis particularly in the kidney are not known. Interestingly, we have discovered an unexpected role for IL-17 in inducing the Kallikrein-Kinin System (KKS) in kidney following candidemia. We also show that overexpression of Klk1 protects IL-17RA-/- mice from candidemia. Kallikreins are serine proteases that cleave kininogens to form bradykinin. The KKS system is known to be involved in renal protection against both acute and chronic kidney injury, but almost no connections of the KKS to candidiasis have been previously reported. The overall goal of this grant application is to determine the underlying mechanisms of IL-17-Klk1 mediated immunity during systemic candidiasis and ultimately to exploit this knowledge for therapeutic benefit. To that end, we will use a series of renal cell type specific gene-targeted mice, global Klk1 and bradykinin receptor-deficient mice and bradykinin receptor agonists to define mechanisms of IL-17-driven renal protection against candidemia (Aim 1). Knowledge gained from these studies will be used in pre-clinical studies to evaluate the therapeutic efficacy of targeting IL-17- KKS axis in kidney specific anti-fungal immunity (Aim 2). Our long term goal is to reduce the morbidity and mortality associated with this devastating hospital acquired infection.

描述（由适用提供）：白色念珠菌是一种位于口腔和肠粘膜中的共生真菌。通常，健康的人类有效控制念珠菌的定殖。但是，在某些情况下，例如固体器官和造血干细胞移植，接受免疫抑制疗法，癌症，早产或居住导管插入术，白色念珠菌可以传播并引起威胁生命的全身性疾病。实际上，传播的念珠菌病是第四大常见的医院感染，死亡率高达40-60％。缺乏有效的疫苗和耐药性发展是成功治疗这些患者的主要限制。因此，严重未满足的临床需求需要开发更好的治疗和预防性策略来打击这些致命的感染。在传播感染期间，念珠菌入侵靶器官，尤其是肾脏和肝脏。大量患者的肾脏不足导致念珠菌死亡。近年来，粘膜免疫系统在抗candida宿主防御方面的贡献已经很好地研究了，但局部免疫在靶器官，尤其是肾脏中的作用很大程度上被忽略了。细胞因子IL-17已成为针对念珠菌物种的宿主防御的关键调解人。人类和实验小鼠模型都缺乏IL-17途径（例如IL-17受体A（IL-17RA））易于传播念珠菌病。我们的初步数据表明，针对全身性念珠菌感染的肾脏防御需要非脊髓囊细胞中的IL-17RA信号传导。然而，尚不清楚IL-17介导的宿主防御系统性念珠菌病的潜在机制，尤其是在肾脏中。有趣的是，我们发现IL-17在念珠菌诱发的肾脏中诱导的Kallikrein-Kinin系统（KKS）中发挥了意想不到的作用。我们还表明，KLK1的过表达保护IL-17RA - / - 小鼠免受念珠菌的影响。 kallikreins是串行蛋白，可清除运动蛋白形成心动激肽。众所周知，KKS系统参与了针对急性和慢性肾脏损伤的肾脏保护，但以前几乎没有KKS与念珠菌病的联系。该赠款应用的总体目标是确定系统性念珠菌病期间IL-17-KLK1介导的免疫学的潜在机制，并最终利用这些知识以获得治疗益处。为此，我们将使用一系列肾细胞类型特异性基因靶向小鼠，全球KLK1和Bradykinin受体缺陷小鼠和松曲蛋白受体受体激动剂来定义IL-17驱动的肾脏保护的机制（AIM 1）。从这些研究中获得的知识将用于临床前研究中，以评估靶向IL-17-KKS轴肾脏特异性抗真菌免疫组织化学的治疗效率（AIM 2）。我们的长期目标是降低与这种毁灭性医院感染相关的发病率和死亡率。