The cell surface mucin MUC1 limits the severity of influenza A virus infection

Abstract

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 À / À 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.

The P2X7 Receptor 489C>T Gain of Function Polymorphism Favors HHV-6A Infection and Associates With Female Idiopathic Infertility

“…HHV-6A recently emerged as a possible determinant of female idiopathic infertility, because infection by this virus alters endometrial immune cell responses and cytokine composition of the uterine milieu (Marci et al, 2016;Caselli et al, 2017;Bortolotti et al, 2019). Furthermore, HHV-6A infection causes a reduction in protein levels of the widely used phenotypic decidualization markers HLA-G (Rizzo et al, 2011) and mucin1 (MUC1) (McAuley et al, 2017). In this study, we explored the role played by the P2X7R in favoring HHV-6A infection and the associated infertility.…”

Novel roles for mucin 1 in the kidney

“…The numerous biological activities attributed to MUC1/Muc1 in promoting cell growth and survival, are sometimes overshadowed by its name and classification as a tethered mucin. MUC1/Muc1 does undergo autocatalytic cleavage early in its biogenesis yielding a large mucin-like subunit (>300 kDa) composed of a variable number of tandem repeats (VNTR, range 40-140) that provides cell surface protection from bacteria, viruses and other environmental insults [5-9]. MUC1 glycans on this subunit also bind to galectins which are associated with crosslinking cell surface proteins and thereby preventing endocytosis [10-12] (Fig.…”

Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

“…The A549 human lung adenocarcinoma epithelial cell line and the Calu-3, a human bronchial epithelial cell line, have been widely used to study influenza virus-host interactions [63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78], viral protein biochemistry [79,80], drug studies [81][82][83] and for performing large-scale screens, such as a CRISPR activation screen, to identify genes that inhibit influenza virus infection when they are overexpressed [82].…”