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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.

项目摘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住院死亡和长期的医院获得性残疾。理解和因此，病毒性肺炎后损害组织修复的靶向机制提供了改善并防止出院后多器官发病。在本项目和PPG中，我们假设甲型流感病毒（IAV）清除后持续的炎症妨碍了适当的肺修复。胞质 NOD样受体蛋白-3（NLRP 3）依赖性炎性体复合物启动成熟形式的炎性细胞因子IL-1 β和IL-18诱导效应细胞募集到感染部位，对清除甲型流感病毒至关重要。此外，单核细胞内的炎性小体激活肺泡巨噬细胞参与甲型流感病毒感染后患者的持续炎症间隙线粒体被认为是NRLP 3依赖性炎性小体的关键调节因子 activation.我们的初步数据表明，抑制线粒体复合物I或III以及给予不改变pH的乳酸钠可减弱炎性小体活化。此外，委员会认为，我们的初步数据表明，流感感染后单核细胞衍生的肺泡巨噬细胞显示出线粒体丙酮酸载体（MPC）mRNA的增加，减少了丙酮酸转化为乳酸，乳酸脱氢酶A（LDHA）。我们将测试是否炎性小体依赖性炎症后病毒小鼠中的清除需要线粒体复合物I和III以及单核细胞来源的使用条件性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得到检验。相关具体目的：（1）线粒体复合体I是否产生甲型流感诱导所需的活性氧单核细胞衍生的肺泡巨噬细胞中NLRP 3依赖的炎性小体激活？(2)是线粒体复合物III产生甲型流感病毒诱导的NLRP 3依赖性炎性小体活化所必需的ROS，单核细胞衍生的肺泡巨噬细胞(3)体内乳酸产生是否降低NLRP 3依赖性单核细胞衍生的肺泡巨噬细胞中甲型流感病毒感染后炎性小体活化。