Project 2: Metabolic regulation of host response and repair mechanisms to influenza A viral pneumonia

项目2：甲型流感病毒性肺炎宿主反应及修复机制的代谢调节

基本信息

批准号：
10269675
负责人：
NAVDEEP S CHANDEL
金额：
$ 50.5万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2021-09-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269675
关键词：
Acute Adult Respiratory Distress Syndrome Alveolar Alveolar Macrophages Attenuated Blood capillaries Cause of Death Cessation of life Clinical Complex Data Dendritic Cells Disease model Effector Cell Electron Transport Electron Transport Complex III Enzymes Epithelial Exudate Failure Floods Functional disorder Funding Opportunities Generations Genetic Glucose Glycolysis Goals Hospitals IL18 gene Immune response Immune signaling Impaired wound healing Impairment Infection Inflammasome Inflammation Inflammatory Influenza Influenza A virus Instruction Interferon Type I Interferons Interleukin-1 Knockout Mice Laboratories Lung Lung infections Membrane Messenger RNA Metabolic Metabolic Control Metabolic Pathway Mitochondria Morbidity - disease rate Mus Natural regeneration Organ Pathology Patients Pharmacology Plasma Process Production Proton Pump Pyruvate Reactive Oxygen Species Recovery Regulation Research Research Personnel Signal Transduction Site Sodium Lactate Specificity Syndrome Testing Time Tissues Viral Viral Load result Viral Pneumonia Virus Virus Diseases Work base conditional knockout cytokine disability functional restoration improved in vivo influenza infection inhibitor/antagonist lactate dehydrogenase A lung repair macrophage monocyte mortality prevent pyruvate carrier receptor recruit repaired response tool

项目摘要

Project summary Viral pneumonia is currently among the most common causes of death in the world. Viral pneumonia impairs tissue repair leading to both in-hospital death and prolonged hospital-acquired disability. Understanding and targeting mechanisms that impair tissue repair after viral pneumonia therefore offers promise to both improve survival and prevent multiple organ morbidity after hospital discharge. In this Project and PPG, we hypothesize that ongoing inflammation after the influenza A virus (IAV) is cleared precludes proper lung repair. The cytosolic NOD-like receptor protein-3 (NLRP3)-dependent inflammasome complex initiates production of mature forms of the inflammatory cytokines IL-1 and IL18, inducing recruitment of effector cells to the site of infection that are essential to clearance of the influenza A virus. In addition, inflammasome activation within the monocyte derived alveolar macrophages participates in the ongoing inflammation observed in patients after influenza A virus clearance. Mitochondria have been proposed to be key regulators of NRLP3 dependent inflammasome activation. Our preliminary data demonstrate that inhibition of mitochondrial complex I or III as well as administration of sodium lactate, which does not alter the pH, attenuates inflammasome activation. Furthermore, our preliminary data indicate that monocyte-derived alveolar macrophages upon influenza infection display an increase in mitochondrial pyruvate carrier (MPC) mRNA, which diminishes pyruvate conversion into lactate by lactate dehydrogenase A (LDHA). We will test whether inflammasome dependent inflammation post-viral clearance in mice requires mitochondrial complexes I and III as well as lactate production in monocyte-derived alveolar macrophages using conditional knockout mice. Collectively these hypotheses will be tested in three interrelated Specific Aims: (1) Is mitochondrial complex I generated ROS required for influenza A induced NLRP3-dependent inflammasome activation in monocyte-derived alveolar macrophages? (2) Is mitochondrial complex III produced ROS necessary for influenza A induced NLRP3-dependent inflammasome activation in monocyte-derived alveolar macrophages? (3) Does in vivo lactate production decrease NLRP3-dependent inflammasome activation following influenza A virus infection in monocyte-derived alveolar macrophages.

项目摘要病毒性肺炎目前是世界上最常见的死亡原因之一。病毒肺炎会损害组织修复会导致院内死亡和长时间医院获得的残疾。理解和靶向损害病毒肺炎后组织修复的靶向机制，因此有望既有改进出院后生存并防止多器官发病。在这个项目和PPG中，我们假设影响力后的病毒（IAV）后正在进行的炎症被清除阻止适当的肺修复。胞质 nod样受体蛋白-3（NLRP3） - 依赖性炎性体复合物启动成熟形式的产生炎性细胞因子IL-1和IL18，诱导效应细胞募集到感染部位对于清除影响病毒至关重要。另外，单核细胞中的炎症体激活肺泡巨噬细胞参与影响病毒后患者中观察到的持续炎症清除。已经提出线粒体是NRLP3依赖性炎性体的关键调节剂激活。我们的初步数据表明，抑制线粒体复合物I或III以及不能改变pH的钠腐蚀剂会减弱炎症体激活。此外，我们的初步数据表明，在造影膜感染时单核细胞衍生的肺泡巨噬细胞显示线粒体丙酮酸载体（MPC）mRNA的增加，从而减少丙酮酸转化为裂解缝合脱氢酶A（LDHA）。我们将测试病毒后炎性疾病是否依赖炎症小鼠的清除需要线粒体复合物I和III以及单核细胞衍生的乳酸产生使用条件敲除小鼠肺泡巨噬细胞。这些假设将在三个中进行检验相互关联的特定目的：（1）是Intractza A诱导的线粒体复合物I所产生的ROS 单核细胞衍生的肺泡巨噬细胞中的NLRP3依赖性炎症体激活？（2）是线粒体复合物III产生了影响力诱导的NLRP3依赖性炎症体激活所必需的ROS 单核细胞衍生的肺泡巨噬细胞？（3）在体内裂缝产生降低NLRP3依赖性影响单核细胞衍生的肺泡巨噬细胞中的病毒感染后的炎症体激活。