Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
School of Chemistry, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia.
Mucosal Immunol. 2017 Nov;10(6):1581-1593. doi: 10.1038/mi.2017.16. Epub 2017 Mar 22.
Cell surface mucin (cs-mucin) glycoproteins are constitutively expressed at the surface of respiratory epithelia where pathogens such as influenza A virus (IAV) gain entry into cells. Different members of the cs-mucin family each express a large and heavily glycosylated extracellular domain that towers above other receptors on the epithelial cell surface, a transmembrane domain that enables shedding of the extracellular domain, and a cytoplasmic tail capable of triggering signaling cascades. We hypothesized that IAV can interact with the terminal sialic acids presented on the extracellular domain of cs-mucins, resulting in modulation of infection efficiency. Utilizing human lung epithelial cells, we found that IAV associates with the cs-mucin MUC1 but not MUC13 or MUC16. Overexpression of MUC1 by epithelial cells or the addition of sialylated synthetic MUC1 constructs, reduced IAV infection in vitro. In addition, Muc1 mice infected with IAV exhibited enhanced morbidity and mortality, as well as greater inflammatory mediator responses compared to wild type mice. This study implicates the cs-mucin MUC1 as a critical and dynamic component of the innate host response that limits the severity of influenza and provides the foundation for exploration of MUC1 in resolving inflammatory disease.
细胞表面黏蛋白（cs-mucin）糖蛋白在呼吸道上皮细胞表面持续表达，流感 A 病毒（IAV）等病原体由此进入细胞。cs-mucin 家族的不同成员均表达一个大而高度糖基化的细胞外结构域，该结构域高于上皮细胞表面的其他受体，其还具有一个跨膜结构域，可使细胞外结构域脱落，以及一个细胞质尾部，能够引发信号级联反应。我们假设 IAV 可以与 cs-mucin 细胞外结构域上呈现的末端唾液酸相互作用，从而调节感染效率。利用人肺上皮细胞，我们发现 IAV 与 cs-mucin MUC1 结合，但不与 MUC13 或 MUC16 结合。上皮细胞中 MUC1 的过表达或添加唾液酸化的合成 MUC1 构建体，均可减少体外 IAV 感染。此外，与野生型小鼠相比，感染 IAV 的 Muc1 小鼠表现出更高的发病率和死亡率，以及更强的炎症介质反应。这项研究表明，cs-mucin MUC1 是先天宿主反应的关键和动态组成部分，可限制流感的严重程度，并为探索 MUC1 治疗炎症性疾病奠定了基础。
