Mechanisms of IL-17 Mediated Host Defense in the Kidney

IL-17 介导的肾脏宿主防御机制

• 批准号: 9023669
• 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
• 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/9023669
• 关键词: A Mouse; 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; Fibrosis; Gene Expression; Gene Targeting; Goals; 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; novel therapeutics; overexpression; pre-clinical; preclinical study; prophylactic; public health relevance; receptor; response; vaccine development

 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.

 性状（由申请方提供）：白色念珠菌是一种寄生于口腔和肠道粘膜的真菌。正常情况下，健康人可以有效地控制念珠菌的定植。然而，在某些情况下，如实体器官和造血干细胞移植，接受免疫抑制治疗，癌症，早产或留置导管，白色念珠菌可传播并导致危及生命的全身性疾病。事实上，播散性念珠菌病是第四常见的医院感染，病死率高达40- 60%。缺乏有效的疫苗和耐药性的发展是成功治疗这些患者的主要制约因素。因此，存在严重的未满足的临床需求，以开发更好的治疗和预防策略来对抗这些致命感染。在播散性感染期间，念珠菌菌丝侵入靶器官，特别是肾脏和肝脏。在相当数量的患者中，肾功能不全导致念珠菌血症死亡。虽然近年来粘膜免疫系统在抗念珠菌宿主防御中的作用已经得到了很好的研究，但局部免疫在靶器官，特别是肾脏中的作用在很大程度上被忽视了。细胞因子IL-17已成为宿主防御念珠菌属物种的关键介质。缺乏IL-17途径如IL-17受体A（IL-17 RA）的人类和实验小鼠模型均易患播散性念珠菌病。我们的初步数据显示，非造血细胞中的IL-17 RA信号传导是肾脏防御系统性念珠菌感染所必需的。然而，IL-17介导的宿主防御系统性念珠菌病的潜在机制，特别是在肾脏是未知的。有趣的是，我们已经发现IL-17在念珠菌血症后诱导肾脏中的激肽释放酶-激肽系统（KKS）中的意想不到的作用。我们还表明Klk 1的过表达保护IL-17 RA-/-小鼠免受念珠菌血症。激肽释放酶是一种丝氨酸蛋白酶，可切割激肽原形成缓激肽。已知KKS系统参与肾脏保护以对抗急性和慢性肾损伤，但以前几乎没有报道KKS与念珠菌病的联系。这项资助申请的总体目标是确定系统性念珠菌病期间IL-17-Klk 1介导的免疫的潜在机制，并最终利用这些知识获得治疗益处。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Klk 1和缓激肽受体缺陷小鼠和缓激肽受体激动剂，以确定IL-17驱动的肾脏保护机制，防止念珠菌血症（目的1）。从这些研究中获得的知识将用于临床前研究，以评价靶向IL-17- KKS轴在肾特异性抗真菌免疫中的治疗效果（目的2）。我们的长期目标是降低与这种毁灭性的医院获得性感染相关的发病率和死亡率。