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

描述（由研究者提供）：本研究的长期目标是了解流感病毒有效感染人类呼吸道的病毒和宿主决定因素。流感病毒是一种影响所有年龄段人群的主要呼吸道病原体，并且是一种永久重新出现的公共卫生威胁，在人群中引起年度流行病和散发性大流行病。尽管流行性感冒的流行，很少有人知道这种病毒如何与其感染的靶组织，人纤毛气道上皮细胞相互作用。人流感病毒结合到气道上皮中的靶纤毛和非纤毛细胞上的含有末端α 2，6-连接的唾液酸的糖缀合物以促进感染，但尚未确定气道中呈递这些唾液酸的相关潜在分子。我们的初步数据表明，人流感病毒与MUC 1上的唾液酸相互作用，MUC 1是一种粘蛋白，系在气道上皮细胞的顶端表面，在整个呼吸道中含量丰富。粘蛋白糖蛋白是粘液的主要成分，并且对于正常的肺功能以及通过捕获颗粒物质和病原体以从气道去除的肺防御是至关重要的。MUC 1与流感病毒相互作用对该病毒发病机制的影响目前尚不清楚。我们假设流感病毒与人体气道表面MUC 1的相互作用会影响流感病毒感染靶上皮细胞的能力。MUC 1可能促进感染（即，充当受体分子），或限制性的（即，作为物理块）。MUC 1还可以启动信号转导途径，导致抗病毒或促炎细胞因子应答，这可能影响流感病毒复制和传播的能力。我们建议使用体外和体内模型系统来确定MUC 1在流感病毒感染中的作用。具体目标1将表征稳定表达人MUC 1的细胞系和MUC 1表达降低或不存在的分化假复层气道上皮模型中的流感病毒结合、进入、复制和扩散以及宿主细胞因子应答。由于MUC 1在流感病毒感染中的作用可能是多因素的，因此特异性目标2将研究野生型小鼠与Muc 1基因缺失小鼠（小鼠同源物）相比的感染和宿主反应的相关性，以确定该粘蛋白对流感病毒发病机制的总体贡献。这项研究将提供流感病毒感染中人类呼吸道主要粘蛋白的全面分析，并为未来研究流感病毒感染模型（如慢性肺病模型）中粘蛋白表达改变提供基础。

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.