The Role of Airway Surface Tethered Mucin 1 in Influenza Virus Infection

描述(由研究人员提供)：这项研究的长期目标是了解允许流感病毒有效感染人类呼吸道的病毒和宿主决定因素。流感病毒是影响所有年龄段的人的一种主要呼吸道病原体，是一种不断出现的公共卫生威胁，在人类人口中造成年度流行和零星流行。尽管流感流行，但人们对这种病毒如何与其感染的目标组织--人类纤毛呼吸道上皮--相互作用知之甚少。人类流感病毒与呼吸道上皮中纤毛细胞和非纤毛细胞上含有末端a2，6-连接唾液酸的糖偶联物结合以促进感染，但在呼吸道中呈现这些唾液酸的相关潜在分子尚未定义。我们的初步数据表明，人类流感病毒与MUC1上的唾液酸相互作用，MUC1是一种粘蛋白，连接在呼吸道上皮细胞的顶端表面，在呼吸道中大量存在。粘蛋白糖蛋白是粘液的主要成分，对于正常的肺功能以及通过捕获颗粒物和病原体从呼吸道清除而进行的肺防御至关重要。MUC1与流感病毒相互作用对该病毒致病机制的影响目前尚不清楚。我们假设流感病毒与人类呼吸道表面的MUC1相互作用影响流感病毒感染靶上皮细胞的能力。MUC1可以促进感染(即，作为受体分子)，也可以是限制性的(即，作为物理障碍)。MUC1还可能启动信号转导通路，导致抗病毒或促炎细胞因子反应，这可能会影响流感病毒的复制和传播能力。我们建议使用体外和体内模型系统来确定MUC1在流感病毒感染中的作用。具体目标1将表征流感病毒的结合、进入、复制和传播以及在稳定表达人MUC1的细胞系和MUC1表达降低或缺失的分化假复层呼吸道上皮模型中宿主细胞因子的反应。由于MUC1在流感病毒感染中的作用可能是多因素的，因此，特殊目标2将研究野生型小鼠与MUC1(小鼠同源基因)基因缺失小鼠的感染和宿主反应的相关性，以确定这种粘蛋白在流感病毒致病中的总体作用。这项研究将对流感病毒感染中人类呼吸道的一种主要粘蛋白进行全面分析，并为未来研究流感病毒在模型中的感染提供基础，例如在慢性肺部疾病模型中，粘蛋白表达发生变化。

DESCRIPTION (provided by the investigator): The long-term goal of this research is to understand the viral and host determinants that allow for efficient infection of the human respiratory tract by influenza viruses. Influenza virus is a major respiratory pathogen affecting people of all ages and a perpetually re-emerging public health threat causing both annual epidemics and sporadic pandemics in the human population. Despite the prevalence of influenza, little is known about how this virus interacts with its target tissue for infection, the human ciliated airway epithelium. Human influenza viruses bind to glycoconjugates containing terminal a2,6-linked sialic acids on target ciliated and non- ciliated cells in the airway epithelium to facilitate infection, yet the relevant underlying molecules in the airway that present these sialic acids have not been defined. Our preliminary data indicate that human influenza viruses interact with sialic acid on MUC1, a mucin protein that is tethered to the apical surface of airway epithelial cells and abundant throughout the respiratory tract. Mucin glycoproteins are a major constituent of mucus and are critical for normal lung function, as well as lung defense by trapping particulate matter and pathogens for removal from the airway. The consequences of MUC1 interaction with influenza virus with respect to the pathogenesis of this virus are currently unknown. We hypothesize that influenza virus interactions with MUC1 on the human airway surface impacts the ability of influenza virus to infect target epithelial cells. MUC1 may be facilitative for infection (i.e., act as a receptor molecule), or restrictive (i.e., act as a physically block). MUC1 may also initiate signal transduction pathways leading to anti-viral or pro-inflammatory cytokine responses that may influence the ability of influenza virus to replicate and spread. We propose to determine the role of MUC1 in influenza virus infection using both in vitro and in vivo model systems. Specific Aim 1 will characterize influenza virus binding, entry, replication and spread as well as the host cytokine response in both cell lines stably expressing human MUC1 and models of differentiated pseudo- stratified airway epithelium in which MUC1 expression is reduced or absent. Because the role of MUC1 in influenza virus infection is likely multi-factoral, Specific Aim 2 will investigate correlates of infection and host response in wild type mice compared to mice genetically deleted for Muc1 (the mouse homolog) to determine the overall contribution of this mucin to influenza virus pathogenesis. This research will provide a comprehensive analysis of a major mucin protein of the human respiratory tract in influenza virus infection and provides the basis for future studies investigating influenza virus infection in models, such as chronic lung disease models, where mucin expression is altered.