Mechanisms of neutrophil dysfunction in antifungal immunity

中性粒细胞功能障碍在抗真菌免疫中的机制

• 批准号: 10454893
• 负责人: Partha Sarathi Biswas
• 金额: $ 48.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454893
• 关键词: Abdomen; Accounting; Adoptive Transfer; Antibiotic Therapy; Antifungal Agents; Bacteria; Biochemical; Biological Assay; Blood; Candida albicans; Cells; Cessation of life; Clinical; Control Animal; Cresol; Data; Defect; Devices; Dialysis procedure; Disease; Disseminated candidiasis; Event; Exhibits; Functional disorder; Generations; Genes; Glucose; Glycogen Synthase Kinases; Glycolysis; Goals; Gut Mucosa; Hemodialysis; Hospitals; Human; Immune System Diseases; Immunity; Immunosuppression; Impairment; In Vitro; Individual; Industrial fungicide; Infection; Intervention; Intestines; Kidney; Kidney Diseases; Knowledge; Leukocyte L1 Antigen Complex; Life; LoxP-flanked allele; Mediating; Medical; Metabolic Pathway; Molecular; Mus; Mycoses; NADPH Oxidase 1; Nosocomial Infections; Operative Surgical Procedures; Oral cavity; PI3K/AKT; Pathway interactions; Patients; Pharmacology; Predisposing Factor; Predisposition; Production; Reactive Oxygen Species; Renal function; Research; Risk Factors; Role; S100A8 gene; Sepsis; Series; Serum; Signal Transduction; Therapeutic; Time; Toxin; Translating; Uremia; Vaccines; clinically relevant; cohort; diagnostic tool; effective therapy; fighting; fungus; glucose uptake; high risk; in vivo; inhibitor; kidney dysfunction; mortality; mortality risk; mouse model; nervous system disorder; neutrophil; novel therapeutic intervention; pre-clinical; preclinical efficacy; prevent; promoter

ABSTRACT Candida albicans is a commensal fungus that resides in the oral cavity and gut mucosa. Normally, healthy individuals efficiently control C. albicans infection. However, in certain pre-disposing conditions such as immunosuppression, antibiotic therapy, abdominal surgery, use of invasive medical interventions or kidney diseases, C. albicans can cause life-threatening disseminated candidiasis (DC). Although hemodialysis is a major cause of bloodstream infection in patients with kidney disease, mortality due to DC is 2 times higher in patients with kidney impairment than individuals without renal dysfunction. Thus, kidney disease is a separate and major risk factor for death from DC in these patients, which has largely been overlooked. It is unknown why patients with renal ailment are inept to fight DC compared to individuals with normal kidney function. Using a clinically relevant mouse model of renal disease, we show that mice with kidney dysfunction are far more susceptible to DC than control animals. Nevertheless, the underlying mechanisms of defect in antifungal immunity in kidney disease are poorly defined. Interestingly, we have discovered an unanticipated role for uremia, characterized by the accumulation of uremic toxin(s) in the blood in the absence of kidney function, in causing neutrophil dysfunction in DC. Our data imply that uremia induces a defect in reactive oxygen species (ROS) generation by neutrophils, which is essential for the elimination of fungi. In part, we show that this is due to a defect in glucose transporter1-mediated uptake of glucose by neutrophils, required for glycolytic pathways upstream of ROS generation. Our hypothesis is that neutrophil-intrinsic impairment in candidacidal function of neutrophils makes uremic patients more susceptible to death from DC. In Aim 1, we will employ series of in vitro and in vivo approaches to define the underlying cellular and molecular mechanisms of defect in glucose uptake and subsequent impairment in ROS production and antifungal activity of neutrophils during uremia. Knowledge gained from these studies will be utilized to identify potential uremic toxin(s) with neutrophil inhibitory activity. We will also device novel therapeutic approaches to correct the abnormalities in cell metabolic pathways and neutrophil dysfunction in kidney diseases. In Aim 2, we will translate and validate our mouse model findings in patients with kidney disease by collecting biospecimens from pre- and post-hemodialysis patients and compare antifungal activity of neutrophils to healthy subjects. The goal of this proposal is to define the mechanisms of defect in antifungal activity of neutrophils in kidney disease and eventually to exploit this information for therapeutic benefit. Our long-term objective is to reduce the mortality associated with this devastating nosocomial infection in patients with kidney disease.

抽象的 白色念珠菌是一种共同的真菌，位于口腔和肠粘膜中。通常情况下， 健康个体有效控制白色念珠菌感染。但是，在某些预先介绍的条件下，例如 免疫抑制，抗生素治疗，腹部手术，使用侵入性医疗干预措施或肾脏 疾病，白色念珠菌会导致威胁生命的散布念珠菌病（DC）。虽然血液透析是 肾脏疾病患者血液感染的主要原因，DC导致死亡率高2倍 肾脏障碍的患者比没有肾功能障碍的人。因此，肾脏疾病是一个独立的 以及这些患者中DC死亡的主要危险因素，这些因素在很大程度上被忽略了。不知道为什么 与肾功能正常的人相比，肾脏疾病患者无能为力。使用 临床上相关的肾脏疾病小鼠模型，我们表明患有肾功能障碍的小鼠更多 比对照动物容易受到直流的影响。然而，抗真菌中缺陷的潜在机制 肾脏疾病的免疫力定义很差。有趣的是，我们发现了一个意外的角色 尿毒症，其特征是在没有肾功能的情况下在血液中积累尿毒症毒素 在DC中引起中性粒细胞功能障碍。我们的数据暗示尿毒症会诱发活性氧的缺陷 （ROS）中性粒细胞产生，这对于消除真菌至关重要。在某种程度上，我们表明这是由于 糖酵解途径所需的中性粒细胞中葡萄糖转运蛋白1介导的葡萄糖摄取的缺陷 ROS生成的上游。我们的假设是，中性粒细胞损伤在念珠化功能中 中性粒细胞使尿毒症患者更容易受到直流死亡的死亡。在AIM 1中，我们将采用一系列体外 并在体内定义葡萄糖摄取缺陷的潜在细胞和分子机制 以及随后在尿毒症期间的ROS产生和中性粒细胞抗真菌活性的损害。知识 从这些研究中获得的将用于鉴定具有中性粒细胞抑制活性的潜在尿毒症毒素。 我们还将采用新颖的治疗方法来纠正细胞代谢途径和 肾脏疾病的中性粒细胞功能障碍。在AIM 2中，我们将在AIM 2中翻译和验证我们的鼠标模型发现 肾脏疾病患者通过从诊断前后患者中收集生物测量并进行比较 中性粒细胞对健康受试者的抗真菌活性。该提议的目的是定义 中性粒细胞在肾脏疾病中的抗真菌活性缺陷，并最终利用这些信息 治疗益处。我们的长期目标是减少与这种毁灭性的死亡率 肾脏疾病患者的医院感染。