Role of alterations in the ATII cell lipidome in influenza pathogenesis

ATII 细胞脂质组变化在流感发病机制中的作用

• 批准号: 9298233
• 负责人: IAN CHRISTOPHER DAVIS
• 金额: $ 51.07万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298233
• 关键词: Acute; Adult Respiratory Distress Syndrome; Antiviral Agents; Apoptosis; Attenuated; Biological Assay; Bronchoalveolar Lavage Fluid; C57BL/6 Mouse; Carbohydrates; Cell Death; Cells; Cessation of life; Choline; Cytidine; Data; Development; Distal; Dysmorphology; Energy Metabolism; Enzymes; Ethanolamines; Generations; Genes; Goals; Hypoxemia; Immune response; Impairment; Infection; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A virus; Ion Transport; Lecithin; Life; Lipids; Lung; Lung diseases; Measures; Metabolism; Methods; Mitochondria; Mitogen-Activated Protein Kinases; Morphology; Mus; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Phosphatidylethanolamine; Phosphatidylglycerols; Phospholipids; Phosphorylation; Phosphorylcholine; Play; Production; Public Health; Pulmonary Edema; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Resources; Respiration; Respiratory physiology; Role; Severities; Site; Supplementation; Testing; Therapeutic Intervention; Time; Vaccines; Virus; Virus Diseases; Virus Replication; alveolar type II cell; base; cell type; clinically relevant; combat; experimental study; fatty acid metabolism; improved; in vivo; influenza epidemic; influenzavirus; lipid metabolism; member; mitochondrial dysfunction; new therapeutic target; novel; pandemic disease; pandemic influenza; patient subsets; phosphoethanolamine; prevent; protein expression; respiratory; seasonal influenza; surfactant; surfactant function; swine flu; tool

Influenza is a highly contagious acute respiratory disease which is of major concern to public health. Severe influenza can trigger acute respiratory distress syndrome (ARDS), for which treatment options are limited. The objective of this proposal is to characterize a novel host determinant that can serve as a target for new drugs to prevent or attenuate development of ARDS in influenza. Alveolar type II (ATII) cells are the site of influenza A virus replication in the distal lung and essential to normal lung function. ATII cells synthesize phospholipids, which are essential for both ATII cell mitochondrial respiration and surfactant function. However, effects of in vivo infection on the ATII cell surfactant lipidome, and their consequences for mitochondrial respiration have not been investigated. Preliminary studies indicate that influenza infection of C57BL/6 mice results in impaired production of CDP-choline and CDP-ethanolamine, which are liponucleotide precursors for de novo synthesis of the major phospholipids (phosphatidylcholine, phosphatidylglycerol, and phosphatidyl- ethanolamine). Development of ARDS is also associated with abnormalities in carbohydrate and fatty acid metabolism, as well as mitochondrial dysfunction and dysmorphology. However, inhibition of CDP-choline synthesis is not a result of reduced expression of CCT-, which catalyzes its production. Influenza-induced ARDS, but not viral replication, is attenuated by post-infection treatment with exogenous liponucleotides. The hypothesis of this proposal is that influenza A virus inhibits ATII cell liponucleotide synthesis, which results in impaired phospholipid generation, reduced surfactant function, altered mitochondrial respiration, and progression to ARDS. This hypothesis will be tested in three complementary Specific Aims, which will show that: 1) Treatment with exogenous lipoNTs attenuates ARDS and improves surfactant function in influenza-infected mice; 2) Disruption of ATII cell Plipid synthesis results in mitochondrial dysfunction, altered energy metabolism, and ATII cell apoptosis; and 3) Impaired ATII cell lipoNT synthesis results from phosphorylation of liponucleotide synthesis enzymes by MAP kinases. Studies will use clinically-relevant measures of ARDS severity and state- of-the-art assays to determine effects of influenza infection on mitochondrial respiration. The goal will be to show a causal relationship between impaired ATII cell phospholipid synthesis, mitochondrial dysfunction, and development of ARDS in influenza-infected mice. Completion of these Aims will generate fundamental new information regarding the role of altered ATII cell lipid metabolism in the pathogenesis of influenza-induced ARDS. It will also provide proof-of-concept that parenteral liponucleotide supplementation can delay onset or reduce severity of influenza-induced ARDS, which will transform our current approach to its treatment.

流感是一种高度传染性的急性呼吸道疾病，是公共卫生的主要关注点。严重 流感可以触发急性呼吸窘迫综合征（ARDS），以便治疗方案有限。这 该建议的目的是表征一个新型宿主确定者，该确定因子可以作为新药的目标 预防或减轻影响力中ARDS的发展。牙槽II型（ATII）细胞是影响力的部位 圆盘肺中的病毒复制，对正常肺功能必不可少。 ATII细胞合成磷脂， 这对于ATII细胞线粒体呼吸和表面活性剂功能都是必不可少的。但是，in in ATII细胞表面活性剂脂肪组的体内感染及其对线粒体呼吸的后果 没有被调查。初步研究表明，影响C57BL/6小鼠的影响会导致受损 CDP-胆碱和CDP-乙醇胺的产生，它们是从头合成的脂核苷酸前体 主要磷脂（磷脂酰胆碱，磷脂酰甘油和磷脂酰乙醇胺） ARDS的发展也与碳水化合物和脂肪酸代谢异常有关 作为线粒体功能障碍和畸形学。但是，抑制CDP-胆碱合成不是结果 CCT-的表达降低，该表达催化其产生。流感引起的ARDS，但没有病毒 复制，通过外源性liponuleotides的感染后治疗减弱。这个假设 提议是影响ATII细胞脂核苷酸合成的影响，这会导致受损 磷脂产生，表面活性剂功能降低，线粒体呼吸改变并发展为 ARDS。该假设将以三个完整的特定目的进行检验，这将表明：1）治疗 外源性liponts可以减弱ARDS并改善影响力的小鼠的表面活性剂功能； 2） ATII细胞plipid合成的破坏会导致线粒体功能障碍，能量代谢改变和 ATII细胞凋亡； 3）liponuleotide磷酸化的ATII细胞Lipont合成受损。 MAP激酶合成酶。研究将使用与临床上的ARDS严重程度和状态相关的措施 确定影响力感染对线粒体呼吸的影响的艺术测定法。目标是 在ATII细胞磷脂合成，线粒体功能障碍和 ARDS感染的小鼠的发展。这些目标的完成将产生基本的新 有关改变ATII细胞脂质代谢在影响ZA诱导的发病机理中的作用的信息 ARDS。它还将提供概念验证，即父母liponuleotide补充可以延迟发作或 减少影响力诱导的ARD的严重程度，这将改变我们当前的治疗方法。