Mechanisms of renal protection against disseminated candidiasis

抵抗播散性念珠菌病的肾脏保护机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的白色念珠菌是一种共生真菌，可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措施。 DC 是第三大最常见的医院获得性疾病感染，死亡率高达 40-60%，并且没有针对这种真菌或任何其他真菌的疫苗。下列的血流感染，念珠菌菌丝侵入并损害肾组织，因肾病而死亡 30-50%的患者存在功能不足。早期诊断、耐药性等方面的挑战阻碍了治疗对保护性免疫的机制了解不足。因此，存在严重未满足的临床需求制定更好的治疗策略来对抗 DC 的肾脏损伤。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。我们发现了意想不到的肾组织 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) 会经历 DC细胞凋亡增加。我们还表明 IL-17 激活激肽释放酶-激肽系统 (KKS)，进而上调受感染肾脏中的肾脏保护性缓激肽。然而，IL-17-的机制缓激肽轴在 DC 中保护 RTEC 免受细胞凋亡的作用尚不清楚。我们的初步数据表明，小鼠缺乏 IL-17 信号传导会导致多种烟酰胺腺嘌呤二核苷酸 (NADH) 的肾表达降低： DC 中的泛醌氧化还原酶基因对线粒体功能至关重要。缺乏 Ndufs 活性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 和缓激肽信号传导汇聚诱导组织型纤溶酶原激活剂 (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，抑制线粒体功能障碍下游的促凋亡事件。这该提案的总体目标是确定 IL-17 缓激肽轴介导肾组织的机制保护 DC 并最终利用这些知识来治疗肾脏损伤。为此，我们将使用 RTEC 特异性删除 CD91 来定义 tPA/CD91 通路在保护 RTEC 免受线粒体功能障碍和细胞凋亡（目标 1A）。我们将询问下游的细胞信号事件 tPA/CD91 通路在真菌感染后防止细胞凋亡的作用（目标 1B）。获得的知识来自这些研究将用于临床前研究，以评估用 tPA 治疗小鼠的治疗效果防止 DC 中的肾脏损伤（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。