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: 9917813
• 负责人: IAN CHRISTOPHER DAVIS
• 金额: $ 74.52万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917813
• 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，对公众健康构成重大关切。严重的

项目成果

Cytidine 5'-Diphosphocholine Corrects Alveolar Type II Cell Mitochondrial Dysfunction in Influenza-infected Mice.

胞苷 5-二磷酸胆碱可纠正流感感染小鼠的肺泡 II 型细胞线粒体功能障碍。

• DOI: 10.1165/rcmb.2021-0512oc
• 发表时间: 2022
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Doolittle,LaurenM;Binzel,Katherine;Nolan,KatherineE;Craig,Kelsey;Rosas,LuciaE;Bernier,MatthewC;Joseph,LisaM;Woods,ParkerS;Knopp,MichaelV;Davis,IanC
• 通讯作者: Davis,IanC