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

基本信息

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
项目类别：
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

项目摘要

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，严重影响公众健康。流感可引发急性呼吸窘迫综合征（ARDS），而治疗选择有限。该提案的目的是描述一种新的宿主决定因素，该决定因素可以作为新药物的靶点预防或减轻流感中 ARDS 的发展 II 型肺泡 (ATII) 细胞是甲型流感病毒的所在地。病毒在远端肺中复制，对正常肺功能至关重要。这对于 ATII 细胞线粒体呼吸和表面活性剂功能至关重要。 ATII 细胞表面活性剂脂质组的体内感染及其对线粒体呼吸的影响初步研究表明，C57BL/6 小鼠的流感感染会导致受损。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然而，CDP-胆碱合成的抑制并不是线粒体功能障碍和形态异常的结果。 CCT-α 的表达减少，其催化流感诱导的 ARDS，但不催化病毒的产生。复制，通过用外源脂核苷酸进行感染后处理而减弱。建议认为甲型流感病毒抑制 ATII 细胞脂核苷酸合成，从而导致受损磷脂的生成、表面活性剂功能的降低、线粒体呼吸的改变以及进展 ARDS。该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 lipoNT 可减轻流感病毒感染小鼠的 ARDS 并改善表面活性剂功能 2) ATII 细胞脂质合成的破坏导致线粒体功能障碍、能量代谢改变和 ATII 细胞凋亡；以及 3) ATII 细胞 lipoNT 合成受损是由脂核苷酸磷酸化造成的研究将使用 ARDS 严重程度和状态的临床相关测量。确定流感感染对线粒体呼吸的影响的最先进的检测方法。显示 ATII 细胞磷脂合成受损、线粒体功能障碍和这些目标的完成将产生根本性的新成果。有关 ATII 细胞脂质代谢改变在流感诱发的发病机制中的作用的信息它还将提供肠外脂核苷酸补充剂可以延迟发作或缓解的概念证明。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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
发表时间：
2022-06
期刊：
影响因子：
6.4
作者：
Doolittle, Lauren M;Binzel, Katherine;Nolan, Katherine E;Craig, Kelsey;Rosas, Lucia E;Bernier, Matthew C;Joseph, Lisa M;Woods, Parker S;Knopp, Michael V;Davis, Ian C
通讯作者：
Davis, Ian C

You Are What You Eat: Diet-Dependent Changes in Pulmonary Surfactant.

人如其食：肺表面活性剂的饮食依赖性变化。