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.

流行性感冒是一种传染性极强的急性呼吸道疾病，对公众健康极为重要。严重 流感可引发急性呼吸窘迫综合征（ARDS），治疗选择有限。的 该提案的目的是表征一种新的宿主决定簇，其可以作为新药的靶点， 预防或减轻流感中ARDS的发展。肺泡II型（ATII）细胞是甲型流感的发病部位 病毒在远端肺中复制，对正常肺功能至关重要。ATII细胞合成磷脂， 其对于ATII细胞线粒体呼吸和表面活性剂功能都是必需的。然而，在 ATII细胞表面活性剂脂质体的体内感染，以及它们对线粒体呼吸的影响， 没有被调查。初步研究表明，C57 BL/6小鼠的流感感染导致受损的 生产CDP-胆碱和CDP-乙醇胺，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的发生也与碳水化合物和脂肪酸代谢异常有关， 线粒体功能障碍和畸形然而，CDP-胆碱合成的抑制不是 减少CCT-β的表达，它催化CCT的产生。流感引起的ARDS，但不是病毒性的 通过用外源性脂核苷酸进行感染后处理来减弱复制。这个假设 一种建议是，甲型流感病毒抑制ATII细胞脂核苷酸合成，这导致受损的 磷脂生成，表面活性剂功能降低，线粒体呼吸改变， ARDS。这一假设将在三个互补的具体目标中进行检验，这将表明：1）治疗 与外源性lipoNTs一起减轻了ARDS并改善了流感感染小鼠的表面活性剂功能; 2） ATII细胞脂质合成的中断导致线粒体功能障碍，能量代谢改变， ATII细胞凋亡;和3）由脂核苷酸磷酸化引起的ATII细胞lipoNT合成受损 MAP激酶合成酶。研究将使用临床相关的ARDS严重程度和状态指标， 确定流感感染对线粒体呼吸的影响的最先进的测定。我们的目标是 显示ATII细胞磷脂合成受损、线粒体功能障碍和 在流感感染的小鼠中发生ARDS。这些目标的实现将产生根本性的新 关于ATII细胞脂质代谢改变在流感诱导的 ARDS。它还将提供概念验证，即胃肠外脂核苷酸补充剂可以延迟发作或 降低流感引起的ARDS的严重程度，这将改变我们目前的治疗方法。