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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：
10696964
负责人：
NAVDEEP S CHANDEL
金额：
$ 49.37万
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/10696964
关键词：
Acute Acute 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 Epithelium 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 Knockout Mice Laboratories Lung Lung infections Macrophage Membrane Messenger RNA Metabolic Metabolic Control Metabolic Pathway Mitochondria Morbidity - disease rate Mus Natural regeneration Organ Pathology Patients 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 conditional knockout cytokine disability functional restoration improved in vivo influenza infection inhibitor lactate dehydrogenase A lung repair monocyte mortality pharmacologic 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.

项目概要病毒性肺炎是目前世界上最常见的死亡原因之一。病毒性肺炎损害组织修复导致院内死亡和长期院内获得性残疾。理解和因此，针对病毒性肺炎后损害组织修复的机制提供了改善两者的希望出院后生存并预防多器官发病。在这个项目和 PPG 中，我们假设甲型流感病毒（IAV）被清除后持续的炎症会妨碍肺部的正常修复。细胞质的 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症细胞因子 IL-1 和 IL18，诱导效应细胞募集至感染部位，对于清除甲型流感病毒至关重要。此外，单核细胞内的炎症小体激活肺泡巨噬细胞参与甲型流感病毒感染后患者体内观察到的持续炎症清除。线粒体被认为是 NRLP3 依赖性炎症小体的关键调节因子激活。我们的初步数据表明，抑制线粒体复合物 I 或 III 以及给予乳酸钠不会改变 pH 值，可减弱炎症小体的激活。此外，我们的初步数据表明，单核细胞来源的肺泡巨噬细胞在流感感染时表现出线粒体丙酮酸载体 (MPC) mRNA 增加，从而减少丙酮酸转化为乳酸乳酸脱氢酶 A (LDHA)。我们将测试病毒后是否存在炎症小体依赖性炎症小鼠体内的清除需要线粒体复合物 I 和 III 以及单核细胞来源的乳酸产生使用条件敲除小鼠的肺泡巨噬细胞。总的来说，这些假设将在三个方面进行检验相互关联的具体目标：（1）线粒体复合物 I 产生的 ROS 是否是甲型流感诱导所需的？单核细胞来源的肺泡巨噬细胞中NLRP3依赖性炎症小体激活？ (2) 是线粒体复合物 III 产生甲型流感诱导的 NLRP3 依赖性炎症小体激活所需的 ROS 单核细胞来源的肺泡巨噬细胞？ (3) 体内乳酸生成是否减少NLRP3依赖性甲型流感病毒感染单核细胞衍生的肺泡巨噬细胞后炎症小体激活。