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

基本信息

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
项目类别：
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

项目摘要

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存在于口腔和肠道粘膜中的共生真菌。通常情况下，健康个体可有效控制白色念珠菌感染。然而，在某些预先处置条件下，例如免疫抑制、抗生素治疗、腹部手术、使用侵入性医疗干预或肾脏治疗疾病，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肾病患者血流感染的主要原因，DC 导致的死亡率是肾病患者的 2 倍肾功能不全的患者比无肾功能不全的患者更重要。因此，肾脏疾病是一个独立的疾病以及这些患者死于 DC 的主要危险因素，但这一点在很大程度上被忽视了。原因不明与肾功能正常的个体相比，肾病患者无法抵抗 DC。使用在临床相关的肾病小鼠模型中，我们发现患有肾功能障碍的小鼠要多得多比对照动物更容易感染 DC。然而，抗真菌缺陷的潜在机制肾脏疾病中的免疫力尚不明确。有趣的是，我们发现了一个意想不到的角色尿毒症，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，引起 DC 中性粒细胞功能障碍。我们的数据表明尿毒症会导致活性氧缺陷（ROS）由中性粒细胞产生，这对于消除真菌至关重要。在某种程度上，我们表明这是由于葡萄糖转运蛋白 1 介导的中性粒细胞对葡萄糖的摄取缺陷，这是糖酵解途径所必需的 ROS 生成的上游。我们的假设是，中性粒细胞的念珠菌功能的内在损伤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和体内方法来定义葡萄糖摄取缺陷的潜在细胞和分子机制以及随后尿毒症期间中性粒细胞的活性氧产生和抗真菌活性受损。知识从这些研究中获得的结果将用于识别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和肾脏疾病中的中性粒细胞功能障碍。在目标 2 中，我们将转化并验证我们的小鼠模型发现通过收集血液透析前和血液透析后患者的生物样本并进行比较中性粒细胞对健康受试者的抗真菌活性。该提案的目标是定义以下机制：肾脏疾病中中性粒细胞抗真菌活性的缺陷，并最终利用该信息治疗益处。我们的长期目标是降低与这一毁灭性灾难相关的死亡率肾病患者的医院感染。