The glycosylated extracellular domain of MUC1 protects against SARS-CoV-2 infection at the respiratory surface

Abstract

Mucus plays an essential role in protecting the respiratory tract against microbial infections. The major components of mucus are heavily O-glycosylated mucin glycoproteins, constitutively expressed at the surface of respiratory epithelia where pathogens enter cells. The gel-forming mucins MUC5AC and MUC5B facilitate the efficient elimination of pathogens by mucociliary clearance. The major role of transmembrane (TM) mucins MUC1, MUC4, and MUC16 are to restrict microbial invasion at the apical surface. SARS-CoV-2 targets respiratory epithelia resulting in an illness spectrum ranging from mild to severe and that the protective role of mucins in infection has not been studied thus far. In this study, we determined the impact of host mucins and mucin glycans on SARS-CoV-2 spike-mediated viral entry into human respiratory cells. Calu-3 human lung epithelial cells have an endogenous expression of the SARS-CoV-2 entry receptor ACE2 and express high levels of the glycosylated transmembrane mucin MUC1. Removal of the mucin glycans sialic acid and fucose from the cellular surface using neuraminidase and fucosidase, respectively, did not significantly impact viral invasion. By contrast, complete removal of the MUC1 extracellular domain of MUC1 using the specific mucinase StcE greatly enhanced spike binding and viral infection. This study implicates the glycosylated extracellular domain of the TM mucin MUC1 as an important component of the host defense that may restrict the severity of SARS-CoV-2 infection.