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: 10673766
• 负责人: Partha Sarathi Biswas
• 金额: $ 48.99万
• 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/10673766
• 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; Fungal Vaccines; Generations; Genes; Glucose; Glucose Transporter; Glycogen Synthase Kinases; Glycolysis; Goals; Gut Mucosa; Hemodialysis; Hospitals; Human; Immune System Diseases; Immunity; Immunosuppression; Impairment; In Vitro; Individual; Infection; Intervention; Intestines; Kidney; Kidney Diseases; Knowledge; Leukocyte L1 Antigen Complex; Life; LoxP-flanked allele; Mediating; Medical; Metabolic Pathway; Molecular; Mus; Mycoses; NADPH Oxidase; Nosocomial Infections; Operative Surgical Procedures; Oral cavity; PI3K/AKT; Pathway interactions; Patients; Predisposing Factor; Predisposition; Production; Reactive Oxygen Species; Renal function; Research; Risk Factors; Role; S100A8 gene; Sepsis; Series; Serum; Signal Transduction; Therapeutic; Toxin; Translating; Uremia; clinically relevant; cohort; diagnostic tool; effective therapy; fighting; fungicide; fungus; glucose uptake; high risk; in vivo; inhibitor; kidney dysfunction; mortality; mortality risk; mouse model; nervous system disorder; neutrophil; novel therapeutic intervention; pharmacologic; pre-clinical; pre-clinical assessment; 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.

摘要 白色念珠菌是一种寄生于口腔和肠道粘膜的真菌。通常情况下， 健康个体有效控制C.白色念珠菌感染然而，在某些预处理条件下， 免疫抑制、抗生素治疗、腹部手术、使用侵入性医疗干预或肾脏 疾病，C.白色念珠菌可引起危及生命的播散性念珠菌病（DC）。虽然血液透析是一种 DC是肾脏疾病患者血流感染的主要原因， 肾功能损害的患者比无肾功能损害的个体多。因此，肾脏疾病是一个单独的 这是这些患者死于DC的主要危险因素，但在很大程度上被忽视了。原因不明 与具有正常肾功能的个体相比，患有肾病的患者不能抵抗DC。使用 临床相关的肾脏疾病小鼠模型，我们表明，肾功能不全的小鼠远远超过 比对照组动物更易感染DC。然而，抗真菌药物缺陷的潜在机制 肾脏疾病中免疫力定义不明确。有趣的是，我们发现了一个意想不到的作用， 尿毒症，其特征是在肾功能缺失的情况下尿毒症毒素在血液中积聚， 导致DC中的中性粒细胞功能障碍。我们的数据表明，尿毒症引起的缺陷，在活性氧 (ROS)由中性粒细胞产生，这是消除真菌所必需的。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葡萄糖转运蛋白1介导的葡萄糖摄取缺陷 ROS生成的上游。我们的假设是，嗜中性粒细胞的杀念珠菌功能的内在损害， 中性粒细胞使尿毒症患者更容易死于DC。在目标1中，我们将采用一系列体外 以及体内方法来确定葡萄糖摄取缺陷的潜在细胞和分子机制 以及尿毒症期间中性粒细胞的ROS产生和抗真菌活性的后续损害。知识 从这些研究中获得的结果将用于鉴定具有中性粒细胞抑制活性的潜在尿毒症毒素。 我们还将设计新的治疗方法来纠正细胞代谢途径的异常， 肾脏疾病中的中性粒细胞功能障碍。在目标2中，我们将翻译和验证我们的小鼠模型发现， 通过收集血液透析前后患者的生物标本， 中性粒细胞对健康受试者的抗真菌活性。本提案的目标是确定 肾脏疾病中中性粒细胞抗真菌活性的缺陷，并最终利用这一信息 治疗益处。我们的长期目标是降低与这种毁灭性疾病相关的死亡率。 肾脏病患者医院感染的研究