Defensive Properties of Mucin Glycoproteins during Respiratory Infections-Relevance for SARS-CoV-2

Abstract

Mucus plays a pivotal role in protecting the respiratory tract against microbial infections. It acts as a primary contact site to entrap microbes and facilitates their removal from the respiratory tract via the coordinated beating of motile cilia. The major components of airway mucus are heavily O-glycosylated mucin glycoproteins, divided into gel-forming mucins and transmembrane mucins. The gel-forming mucins MUC5AC and MUC5B are the primary structural components of airway mucus, and they enable efficient clearance of pathogens by mucociliary clearance. MUC5B is constitutively expressed in the healthy airway, whereas MUC5AC is upregulated in response to inflammatory challenge. MUC1, MUC4, and MUC16 are the three major transmembrane mucins of the respiratory tracts which prevent microbial invasion, can act as releasable decoy receptors, and activate intracellular signal transduction pathways. Pathogens have evolved virulence factors such as adhesins that facilitate interaction with specific mucins and mucin glycans, for example, terminal sialic acids. Mucin expression and glycosylation are dependent on the inflammatory state of the respiratory tract and are directly regulated by proinflammatory cytokines and microbial ligands. Gender and age also impact mucin glycosylation and expression through the female sex hormone estradiol and age-related downregulation of mucin production. Here, we discuss what is currently known about the role of respiratory mucins and their glycans during bacterial and viral infections of the airways and their relevance for the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the impact of microbe-mucin interaction in the respiratory tract could inspire the development of novel therapies to boost mucosal defense and combat respiratory infections.

Keywords: MUC1; O-linked glycans; SARS-CoV-2; glycosylation; mucin; mucin-microbe interactions; mucosal barrier; respiratory pathogens.

FIG 1

Mucosal defense in the respiratory tract during SARS-CoV-2 infection. (A) Human upper and lower respiratory tracts. (B) Respiratory epithelium with ciliated cells, goblet cells, and a submucosal gland. The soluble mucin MUC5AC is secreted by goblet cells, and the soluble mucin MUC5B is secreted by mucosal cells in the submucosal gland. (C) Ciliated epithelial cells express transmembrane mucins MUC1 (red), MUC4 (blue), and MUC16 (yellow) and the SARS-CoV-2 entry receptor ACE2. (D) Domain structure of transmembrane mucins MUC1, MUC4, and MUC16. Mucin O-glycan structures and, specifically, terminal sialic acids play an important role in virus-mucin interactions.