Mechanisms of IL-17 Mediated Host Defense in the Kidney

 描述(申请人提供)：白色念珠菌是一种共生真菌，存在于口腔和肠道粘膜中。正常情况下，健康的人类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、早产或留置导尿术，白色念珠菌可传播并引起危及生命的系统性疾病。事实上，播散性念珠菌病是第四种最常见的医院感染，死亡率高达40%-60%。缺乏有效的疫苗和耐药性的产生是成功治疗这些患者的主要制约因素。因此，有一个严重的未得到满足的临床需要，即开发更好的治疗和预防策略来对抗这些致命的感染。在播散性感染过程中，假丝酵母菌侵袭靶器官，特别是肾脏和肝脏。在相当数量的患者中，死于念珠菌血症的原因是肾功能不全。近年来，虽然粘膜免疫系统在抗念珠菌宿主防御中的作用得到了很好的研究，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已成为宿主抵抗念珠菌的关键介质。IL-17受体A(IL-17RA)等IL-17途径缺陷的人和实验小鼠模型均易患播散性念珠菌病。我们的初步数据表明，非造血细胞中的IL-17RA信号是肾脏抵御系统性念珠菌感染所必需的。然而，IL-17介导的宿主对系统性念珠菌病的潜在防御机制尚不清楚，特别是在肾脏。有趣的是，我们发现IL-17在白念珠菌血症后肾脏中诱导激肽释放酶-激肽释放酶系统(KKS)中有一个意想不到的作用。我们还发现过表达Klk1可以保护IL-17RA-/-小鼠免受念珠菌血症的侵袭。激肽释放酶是一种丝氨酸蛋白酶，能裂解激肽原形成缓激肽。众所周知，KKS系统参与了对急性和慢性肾损伤的肾脏保护，但以前几乎没有报道过KKS与念珠菌病的联系。这项赠款申请的总体目标是确定系统性念珠菌病期间IL-17-KLK1介导的免疫的潜在机制，并最终利用这一知识为治疗带来好处。为此，我们将使用一系列肾细胞类型特异性基因靶向小鼠、全局Klk1和缓激肽受体缺陷小鼠以及缓激肽受体激动剂来确定IL-17驱动的肾脏保护机制，以防止念珠菌血症(目标1)。从这些研究中获得的知识将被用于临床前研究，以评估靶向IL-17-KKS轴在肾脏特异性抗真菌免疫中的治疗效果(目标2)。我们的长期目标是减少与这种毁灭性的医院获得性感染相关的发病率和死亡率。

 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.