Membrane-Tethered Mucin 1 Is Stimulated by Interferon and Virus Infection in Multiple Cell Types and Inhibits Influenza A Virus Infection in Human Airway Epithelium.

Abstract

ABSTRACTInfluenza A virus (IAV) causes significant morbidity and mortality in the human population. Tethered mucin 1 (MUC1) is highly expressed in airway epithelium, the primary site of IAV replication, and also by other cell types that influence IAV infection, including macrophages. MUC1 has the potential to influence infection dynamics through physical interactions and/or signaling activity, yet MUC1 modulation and its impact during viral pathogenesis remain unclear. Thus, we investigated MUC1-IAV interactions in an in vitro model of human airway epithelium (HAE). Our data indicate that a recombinant IAV hemagglutinin (H3) and H3N2 virus can bind endogenous HAE MUC1. Notably, infection of HAE with H1N1 or H3N2 IAV strains does not trigger MUC1 shedding but instead stimulates an increase in cell-associated MUC1 protein. We observed a similar increase after type I or III interferon (IFN) stimulation; however, inhibition of IFN signaling during H1N1 infection only partially abrogated this increase, indicating that multiple soluble factors contribute to MUC1 upregulation during the antiviral response. In addition to HAE, primary human monocyte-derived macrophages also upregulated MUC1 protein in response to IFN treatment and conditioned media from IAV-infected HAE. Then, to determine the impact of MUC1 on IAV pathogenesis, we developed HAE genetically depleted of MUC1 and found that MUC1 knockout cultures exhibited enhanced viral growth compared to control cultures for several IAV strains. Together, our data support a model whereby MUC1 inhibits productive uptake of IAV in HAE. Infection then stimulates MUC1 expression on multiple cell types through IFN-dependent and -independent mechanisms that further impact infection dynamics.