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

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