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: 10376250
• 负责人: Partha Sarathi Biswas
• 金额: $ 19.65万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376250
• 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; 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; diagnostic tool; fungus; in vivo; inhibitor; insight; mitochondrial dysfunction; mortality; new therapeutic target; novel; pathogenic fungus; pre-clinical; preclinical study; prevent; receptor; renal damage; therapeutically effective

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 白色念珠菌是一种肠道真菌，通过留置引起严重的播散性念珠菌病（DC 导管、腹部手术或其他临床干预。DC是第三常见的医院获得性 感染，死亡率高达40- 60%，并且没有针对这种或任何其他真菌的疫苗。以下 血液感染，念珠菌菌丝侵入并损害肾组织，死亡率是由于肾 30%-50%的患者存在功能不全。治疗受到早期诊断、耐药性 以及对保护性免疫力的机械理解不足。因此，存在严重未满足的临床需求， 开发更好的治疗策略来对抗DC的肾损伤。促炎细胞因子白细胞介素- 17（IL-17）已成为抗真菌免疫的关键介质。我们发现了一个意外的肾脏组织 IL-17在DC中的保护作用。在缺乏IL-17信号传导的情况下，肾小管上皮细胞（RTEC）经历了 增加DC的凋亡。我们还发现IL-17激活激肽释放酶-激肽系统（KKS）， 在受感染的肾脏中上调肾脏保护性缓激肽。然而，IL-17- 缓激肽轴在DC中保护RTEC免于凋亡性细胞死亡的作用尚不清楚。我们的初步数据显示， 缺乏IL-17信号传导表现出多种烟酰胺腺嘌呤二核苷酸（NADH）的肾表达降低： 泛醌氧化还原酶基因在DC中，这是线粒体功能的关键。Ndufs活动缺乏 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。RTEC中的IL-17和缓激肽信号传导 聚集以诱导组织型纤溶酶原激活剂（tPA），这是一种已知可以阻止激活的丝氨酸蛋白酶 通过与细胞表面受体CD 91的结合，在线粒体功能障碍的下游发生促凋亡事件。的 本提案的总体目标是确定IL-17-缓激肽轴介导的肾组织的机制， 保护DC，并最终利用这些知识治疗肾损伤。为此，我们将 使用RTEC特异性CD 91缺失来定义tPA/CD 91途径在保护RTEC免受 线粒体功能障碍和细胞凋亡（Aim 1A）。我们将研究下游的细胞信号事件 tPA/CD 91通路在真菌感染后抗细胞凋亡中的作用（目的1B）。获得的消息 这些研究将用于临床前研究，以评价用tPA治疗小鼠的治疗效果， 防止DC中的肾损伤（目的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感染有关

项目成果

Local antifungal immunity in the kidney in disseminated candidiasis.

• DOI: 10.1016/j.mib.2021.04.005
• 发表时间: 2021-08
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Jawale CV;Biswas PS
• 通讯作者: Biswas PS