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，是公众健康的主要关注点。严重者 流感可引发急性呼吸窘迫综合征(ARDS)，其治疗选择有限。这个 这项建议的目的是表征一种新的宿主决定簇，它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)细胞是甲型流感的部位 病毒在远端肺中复制，对正常肺功能是必不可少的。ATII细胞合成磷脂， 它们对ATII细胞线粒体呼吸和表面活性物质的功能都是必不可少的。然而，In的影响 ATII细胞表面活性物质脂质体上的活体感染及其对线粒体呼吸的影响 没有被调查过。初步研究表明，C57BL/6小鼠感染流感可导致 从头合成的脂核苷酸前体CDP-胆碱和CDP-乙醇胺的生产 主要的磷脂(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的异常有关 线粒体功能障碍和畸形。然而，抑制CDP-胆碱的合成并不是结果 减少Cct-的表达，从而催化其产生。流感引起的ARDS，但不是病毒 复制，通过感染后用外源脂核苷酸处理来减弱。这是一个假设 有人提出，甲型流感病毒抑制ATII细胞脂核苷酸合成，从而导致 磷脂生成，表面活性物质功能降低，改变线粒体呼吸，并进展为 阿兹。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 外源性脂纳米管减轻流感感染小鼠的ARDS并改善表面活性物质功能；2) ATII细胞磷脂合成中断导致线粒体功能障碍，能量代谢改变，以及 ATII细胞凋亡；以及3)脂核苷酸磷酸化导致ATII细胞脂NT合成受损 由MAP激酶合成的酶。研究将使用与临床相关的ARDS严重程度和状态的测量- 最先进的检测方法来确定流感感染对线粒体呼吸的影响。目标将是 显示ATII细胞磷脂合成受损、线粒体功能障碍和 ARDS在流感感染小鼠中的发展。完成这些目标将产生根本性的新的 ATII细胞脂代谢改变在流感发病机制中作用的研究进展 阿兹。它还将提供概念证明，即肠外补充脂核苷酸可以推迟发病或 降低流感引起的ARDS的严重性，这将改变我们目前的治疗方法。

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