Mechanisms of renal protection against disseminated candidiasis

抵抗播散性念珠菌病的肾脏保护机制

• 批准号: 10190010
• 负责人: Partha Sarathi Biswas
• 金额: $ 23.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-22 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190010
• 关键词: Abdomen; Alteplase; Antifungal Agents; Antifungal Therapy; Apoptosis; Apoptotic; Autopsy; Binding; Bradykinin; Candida; Candida albicans; Cell Death; Cell Surface Receptors; Cells; Cessation of life; Clinical; Complex; Data; Diagnostic; Disseminated candidiasis; Distal; Drug resistance; Early Diagnosis; Electron Transport; Epithelial Cells; Event; Exhibits; Fatality rate; Gene Family; Genes; Goals; Grant; Hyphae; Immune; Immunity; Indwelling Catheter; Interleukin-17; Intervention; Invaded; Ischemic Stroke; Kallikrein-Kinin System; Kidney; Kidney Failure; Knock-out; Knockout Mice; Knowledge; Link; Mediating; Mediator of activation protein; Membrane Potentials; Mitochondria; Modality; Morbidity - disease rate; Mus; Mycoses; Nicotinamide adenine dinucleotide; Nosocomial Infections; Nuclear; Operative Surgical Procedures; Organ; Outcome; Oxidative Phosphorylation; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Plasminogen Activator; Pre-Clinical Model; Predisposition; Preventive; Recombinants; Renal Tissue; Renal function; Respiratory Chain; Role; Scheme; Sepsis; Serine Protease; Signal Pathway; Signal Transduction; Stimulus; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tubular formation; Ubiquinone; Vaccines; Vasodilator Agents; Wild Type Mouse; cell injury; combat; conditional knockout; cytokine; fungus; in vivo; inhibitor/antagonist; insight; mitochondrial dysfunction; mortality; new therapeutic target; novel; pathogenic fungus; pre-clinical; preclinical study; prevent; receptor; renal damage; therapeutically effective; tool

ABSTRACT Candida albicans is a commensal fungus that causes severe disseminated candidiasis (DC) via indwelling catheters, abdominal surgery or other clinical interventions. DC is the 3rd most common hospital-acquired infection, with fatality rates up to 40-60%, and there are no vaccines to this or any other fungi. Following bloodstream infection, Candida hyphae invades and damages kidney tissue, and mortality is due to renal insufficiency in 30-50% of the patients. Treatment is hampered by challenges in early diagnosis, drug resistance, and a poor mechanistic understanding of protective immunity. Hence, there is a serious unmet clinical need to develop better therapeutic strategies to combat kidney damage in DC. The proinflammatory cytokine Interleukin- 17 (IL-17) has emerged as a key mediator of antifungal immunity. We discovered an unexpected renal tissue protective role for IL-17 in DC. In the absence of IL-17 signaling, renal tubular epithelial cells (RTEC) undergo increased apoptosis in DC. We also showed that IL-17 activates Kallikrein-Kinin System (KKS) which in turn upregulates kidney protective bradykinin in the infected kidney. However, the mechanisms by which IL-17- bradykinin-axis protects RTEC from apoptotic cell death in DC is unknown. Our preliminary data show that mice lacking IL-17 signaling exhibit reduced renal expression of multiple nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase genes in DC, which are critical for mitochondrial function. The lack of Ndufs activity is associated with mitochondrial dysfunction, a key driver of apoptosis. IL-17 and bradykinin signaling in RTEC converge to induce tissue type plasminogen activator (tPA), a serine protease known to prevent the activation of pro-apoptotic events downstream of mitochondrial dysfunction via binding to cell surface receptor CD91. The overall goal of this proposal is to determine the mechanisms of IL-17-bradykinin-axis mediated kidney tissue protection in DC and ultimately to utilize this knowledge for the treatment of kidney damage. To that end, we will use RTEC specific deletion of CD91 to define the role for tPA/CD91 pathway in protecting RTEC from mitochondrial dysfunction and apoptosis (Aim 1A). We will interrogate the cellular signaling events downstream of tPA/CD91 pathway in protection against apoptosis following fungal infection (Aim 1B). Knowledge gained from these studies will be used in pre-clinical studies to evaluate the therapeutic efficacy of treating mice with tPA in protection against the kidney damage in DC (Aim 2). Our long-term goal is to reduce the morbidity and mortality associated with this devastating hospital-acquired infection.

摘要 白色念珠菌是一种通过留置引起严重播散性念珠菌病(DC)的共生真菌。 导尿管、腹部手术或其他临床干预措施。DC是第三大最常见的医院获得者 感染，致死率高达40%-60%，而且没有针对这种或任何其他真菌的疫苗。跟随 血液感染，假丝酵母菌侵袭和破坏肾脏组织，死亡原因是肾脏 30%-50%的患者存在功能不全。治疗受到早期诊断、耐药性、 对保护性免疫的机械理解也很差。因此，有一个严重的未得到满足的临床需求 制定更好的治疗策略来对抗DC的肾脏损害。促炎细胞因子白介素2 17(IL-17)已成为抗真菌免疫的关键介质。我们发现了一个意想不到的肾组织 IL-17在DC中的保护作用。在没有IL-17信号的情况下，肾小管上皮细胞(RTEC)经历 树突状细胞凋亡率增加。我们还发现，IL-17激活激肽释放酶-激肽释放酶系统(KKS)，进而 在受感染的肾脏中上调肾脏保护性缓激肽。然而，IL-17- 缓激素轴在DC中保护RTEC免受凋亡细胞死亡的影响尚不清楚。我们的初步数据显示，老鼠 缺乏IL-17信号显示肾脏多个烟酰胺腺嘌呤二核苷酸(NADH)表达减少： DC中的泛醌氧化还原酶基因，对线粒体功能至关重要。缺乏核发展援助框架的活动 与线粒体功能障碍有关，线粒体功能障碍是细胞凋亡的关键驱动因素。IL-17与缓激肽在RTEC中的信号转导 聚合以诱导组织型纤溶酶原激活物(TPA)，这是一种已知可防止激活的丝氨酸蛋白酶 通过与细胞表面受体CD91结合，在线粒体功能障碍下游发生促凋亡事件。这个 这项建议的总体目标是确定IL-17-缓激素轴介导的肾组织的机制 在DC的保护，并最终利用这一知识治疗肾损害。为此，我们将 使用RTEC特异性的CD91缺失来确定tPA/CD91通路在保护RTEC中的作用 线粒体功能障碍和细胞凋亡(目标1A)。我们将询问下游的蜂窝信号事件 研究tPA/CD91通路在抗真菌感染后细胞凋亡中的作用(目标1B)。从以下方面获得的知识 这些研究将用于临床前研究，以评估tPA对小鼠的治疗效果。 DC对肾脏损伤的保护(目标2)。我们的长期目标是降低发病率和死亡率。 与这种毁灭性的医院获得性感染有关。