Surfactant Lipid and Protein Inhibition of Rhinovirus Infections

表面活性剂脂质和蛋白质对鼻病毒感染的抑制作用

• 批准号: 10261955
• 负责人: DENNIS R. VOELKER
• 金额: $ 33.26万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10261955
• 关键词: Acute; Adult; Affinity; Air; Alleles; Animals; Antiviral Agents; Asthma; Attenuated; Binding; Cadherins; Cell Surface Receptors; Cell surface; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Clinical Research; Collaborations; Collection; Complex; Cystic Fibrosis; Data; Data Set; Economic Burden; Epithelial Cells; Evaluation; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Homologous Gene; Hospitalization; Human; Immunization; Infection; Inflammation; Inflammatory; Inflammatory Response Pathway; Influenza A virus; Innate Immune System; Interferons; Interstitial Lung Diseases; Irrigation; Lead; Learning; Length; Letters; Ligands; Lipids; Liquid substance; Lung; Lung diseases; Mediating; Minor; Mus; Nasal Epithelium; Natural Immunity; Outcome; Participant; Patients; Phosphatidylglycerols; Phosphatidylinositols; Phospholipids; Play; Prevention; Process; Production; Prophylactic treatment; Protein Inhibition; Protein Isoforms; Proteins; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Pyroglyphidae; Reagent; Receptor Activation; Refractory; Replication-Associated Process; Respiratory syncytial virus; Rhinovirus; Rhinovirus infection; Role; Serotyping; Serum; Site; Structure; Subgroup; System; Therapeutic; Toll-like receptors; Transcription Process; Transgenic Mice; Variant; Viral; Viral Load result; Viral Physiology; Viral Respiratory Tract Infection; Virion; Virulence; Virulent; Virus; Virus Diseases; Virus Replication; Wheezing; Whole Organism; Work; analog; anti-viral efficacy; asthma exacerbation; asthmatic; asthmatic patient; burden of illness; cilium motility; early childhood; experimental study; genetic variant; human coronavirus; improved; in vivo; mouse model; novel; patient population; prevent; programs; replication factor C; response; surfactant; targeted agent; targeted treatment; transcriptome; transcriptome sequencing; viral entry inhibitor

Rhinoviruses (RVs) play a major role in causing asthma exacerbations, which drive disease and economic burdens. Among the RVs the RV-C subgroup is especially problematic, due to its virulence. This proposal is focused on RV-C, and ameliorating its effects with anti-viral agents derived from pulmonary surfactant lipids and proteins. Two minor anionic phospholipids of pulmonary surfactant, palmitoyl-oleoyl- phosphatidylglycerol (POPG) and phosphatidylinositol (PI), antagonize respiratory viral infections and suppress inflammatory sequelae triggered by Toll-like receptor activation, by acting as decoy ligands. In addition, the pulmonary surfactant protein, SP-A, also disrupts RV-C infections, in part by direct interactions with virions. In this proposal we plan to investigate the mechanisms by which surfactant lipids and proteins inhibit RV infections and replication. In Aim 1, we will examine how POPG and PI and their structural analogs interfere with RV-C infection/replication using Air-Liquid Interface (ALI) cultures. Our current data support a mechanism in which the lipids act intracellularly to alter the infection/replication processes. Indeed, preliminary RNAseq data suggest that PI interferes with ciliagenesis, rendering host cells refractory to being infected; since infection requires mature, motile cilia. The same RNAseq data set also suggests that POPG acts at a different intracellular site from PI. Transgenic mouse studies are also proposed in Aim 1 and will investigate the efficacy of the anti-viral phospholipids in the context of the whole organism. In Aim 2, we will investigate how SP-A disrupts RV-C infection/replication using Air-Liquid-interface cultures ex vivo. We will also perform RNAseq analysis to probe the host cell and viral transcriptomes. We will use our collection of purified SP-A isoforms to determine the rank order potency of different SP-A structural variants both ex vivo and in vivo. The ex vivo SP- A studies will be expanded to studies in transgenic mice to understand the actions of SP-A in the context of an intact lung and whole animal. From the experiments described in this proposal we anticipate learning the mechanisms of action of surfactant lipids and proteins as anti-viral agents targeting RVs that aggravate asthma and cause exacerbations. We expect this information will identify novel reagents for controlling RV infections in humans, and lead to new data that will improve the actions of the surfactant constituents.

鼻病毒（RVS）在引起疾病和经济的哮喘加重方面起着重要作用 负担。在RVS中，RV-C子组由于其毒力而尤其有问题。这个建议 专注于RV-C，并改善其对源自肺部表面活性剂脂质的抗病毒剂的作用 和蛋白质。肺表面活性剂的两种小阴离子磷脂 磷脂酰甘油（POPG）和磷脂酰肌醇（PI），拮抗呼吸道病毒感染和 抑制炎症后遗症是由Toll样受体激活触发的，通过充当诱饵配体。 另外，肺表面活性剂蛋白SP-A也会破坏RV-C感染，部分地是直接 与病毒体的相互作用。在此提案中，我们计划研究表面活性剂脂质的机制 蛋白质抑制RV感染和复制。在AIM 1中，我们将研究POPG和PI及其结构 类似物使用空气界面（ALI）培养物干扰RV-C感染/复制。我们当前的数据 支持脂质细胞内作用以改变感染/复制过程的机制。的确， 初步的RNASEQ数据表明，PI会干扰纤毛，使宿主细胞难以耐药至 已感染;由于感染需要成熟的纤毛。相同的RNASEQ数据集也表明POPG ACT 在与PI不同的细胞内部位。在AIM 1中也提出了转基因小鼠研究，并将研究 在整个生物体的背景下，抗病毒磷脂的功效。在AIM 2中，我们将调查如何 SP-A使用空气 - 插头培养物在体内破坏RV-C感染/复制。我们还将执行RNASEQ 分析以探测宿主细胞和病毒转录组。我们将使用纯化的SP-A同工型收集到 确定离体和体内不同SP-A结构变体的等级顺序效力。 ex vivo sp- 一项研究将扩展到转基因小鼠的研究，以了解SP-A的作用 完整的肺和全动物。从本提案中描述的实验中，我们期望学习 表面活性剂脂质和蛋白质的作用机理，作为靶向RVS的抗病毒剂，加剧哮喘 并引起恶化。我们希望这些信息将确定用于控制RV感染的新试剂 在人类中，并导致新数据将改善表面活性剂成分的作用。