Molecular Mechanisms and In Vivo Impact of Tethered Mucin 1-Influenza Virus Interactions

系留粘蛋白 1-流感病毒相互作用的分子机制和体内影响

• 批准号: 10327722
• 负责人: Margaret Adele Scull
• 金额: $ 61.8万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327722
• 关键词: Address; Affect; Age; Amino Acids; Apical; Atlases; Bacterial Infections; Binding; Biological Assay; Biological Models; Biology; Bone Marrow; Cell Compartmentation; Cell Culture Techniques; Cell surface; Cells; Cellular Structures; Clinical; Conflict (Psychology); Consensus; Cytoplasmic Tail; Data; Disease; Epidemic; Epithelial Cells; Flow Cytometry; Gel; Genetic Transcription; Glycoproteins; Goals; Hematopoietic; Human; Immune response; Immunohistochemistry; In Vitro; Individual; Infection; Inflammation; Influenza A virus; Interferons; Investigation; Kinetics; Knockout Mice; Laboratories; Lung; Malignant Neoplasms; Mass Spectrum Analysis; Mediation; Modeling; Molecular; Morbidity - disease rate; Mucin 1 protein; Mucins; Mucous body substance; Mus; Nature; Outcome; Pathogenesis; Pathogenicity; Persons; Phosphorylation; Physiological; Population; Proteins; Public Health; Reporting; Research; Respiratory System; Role; Sialic Acids; Signal Transduction; Signaling Molecule; Stable Isotope Labeling; Surface; System; Technology; Testing; Time; Tracheal Epithelium; Up-Regulation; Viral; Viral Pathogenesis; Virus Diseases; Virus Replication; acute infection; airway epithelium; base; cell type; defined contribution; glycosylation; in vivo; in vivo Model; influenzavirus; innovation; insight; macrophage; mortality; mouse model; novel; pandemic disease; pathogen; pathogenic virus; preference; respiratory pathogen; therapeutic target; tumor progression; uptake

ABSTRACT To infect airway epithelial cells, influenza A virus (IAV) must penetrate the secreted mucus and underlying periciliary layer barriers – both comprised, in large part, of mucin glycoproteins that can be secreted or tethered to the apical surface of cells. The importance of tethered mucins in various disease states and acute infection is increasingly being realized. Specifically, tethered mucin 1 (MUC1) has been implicated in various aspects of both bacterial and viral infections. However, these reports do not yield consensus on MUC1 function during pathogenic insult and while it seems logical to assume that MUC1 expression would benefit the host, our preliminary data indicate that MUC1 facilitates IAV infection. As MUC1 is expressed by multiple cell types that influence IAV pathogenesis, including airway epithelial cells and macrophages, and has been proposed to act as both a structural barrier and signaling molecule, we hypothesize that MUC1 facilitates IAV infection through multiple mechanisms, involving both physical and functional attributes of MUC1, and multiple cell types. We will test this hypothesis by pursing two specific aims: 1) Define the contribution of MUC1 expression in specific cell compartments to IAV pathogenesis and 2) Define MUC1 molecular interactions and intracellular dynamics in human airway epithelium during IAV infection. Aim 1 will generate a MUC1-expression atlas in the lung during infection, determine the impact of MUC1 expression on IAV infection of both human and mouse primary airway epithelial cells, and define the contribution of MUC1 expression in specific cell compartments to the outcome of infection in vivo. Aim 2 will interrogate the physical interaction between IAV and MUC1 in physiologically relevant models of airway epithelium and define the impact of IAV and interferon on MUC1 expression, activation, and interacting partners through mechanistic studies and comprehensive mass spectrometry-based technology. This research is innovative in its use of novel in vitro and in vivo models with altered MUC1 expression to dissect the interplay between IAV and MUC1 at both the molecular and organismal level. Our results will be significant as defining MUC1 function in the context of IAV infection will advance our understanding of tethered mucin biology and reveal mechanisms of how IAV negotiates specific mucin molecules to efficiently infect the respiratory tract.

摘要 要感染呼吸道上皮细胞，甲型流感病毒(IAV)必须穿透分泌的粘液和 睫状层屏障--两者主要由可分泌或捆绑的粘蛋白糖蛋白组成。 到细胞的顶端表面。束缚粘蛋白在各种疾病状态和急性感染中的重要性 正越来越多地被实现。具体地说，拴系粘蛋白1(MUC1)与多种因素有关。 包括细菌和病毒感染。然而，这些报告并未就MUC1的功能达成共识 致病性侮辱和虽然似乎合乎逻辑的假设，MUC1的表达将有益于宿主，我们的 初步数据表明，MUC1促进了IAV感染。因为MUC1由多种细胞类型表达， 影响IAV的发病机制，包括呼吸道上皮细胞和巨噬细胞，并已被提出发挥作用 作为一个结构屏障和信号分子，我们推测MUC1通过以下途径促进IAV感染 多种机制，涉及MUC1的物理和功能属性，以及多种细胞类型。我们 我将通过追求两个具体目标来检验这一假说：1)确定MUC1在特定情况下的表达贡献 与IAV致病相关的细胞室和2)确定MUC1分子相互作用和细胞内动力学 在IAV感染期间的人呼吸道上皮细胞中。AIM 1将在肺内生成MUC1表达图谱 在感染过程中，确定MUC1表达对人和小鼠原代IAV感染的影响 并确定在特定的细胞室中MUC1的表达对 体内感染的结局。目标2将询问IAV和MUC1之间的物理相互作用 生理相关的呼吸道上皮细胞模型及IAV和干扰素对MUC1的影响 通过机制研究和全面的质量来表达、激活和互动伙伴 基于光谱的技术。这项研究在使用新的体外和体内模型方面具有创新性 改变MUC1的表达以剖析IAV和MUC1在分子和分子水平上的相互作用 生物体水平。我们的结果将具有重要意义，因为在IAV感染的背景下定义MUC1功能将 促进我们对拴系粘蛋白生物学的理解，并揭示IAV如何谈判特定的 粘蛋白分子可以有效地感染呼吸道。