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.

Immunological and cardio-vascular pathologies associated with SARS-CoV-2 infection in golden syrian hamster

“…Furthermore, the expression of eotaxin, a CC chemokine and a potent chemoattractant for airway eosinophils and mast cells that is particularly elevated in asthma and allergy conditions, was upregulated at 2 dpi ( Figure 2G ) (Guo et al, 2001). The expression of other lung injury markers like mucin (muc-1: marker of respiratory infections), surfactant protein-D (sftp-D: acute lung injury marker), advanced glycation end product (AGER: pro-inflammatory pattern recognition receptor) and plasmonigen activator inhibitor-I (PAI-1: a key factor for lung fibrosis) was upregulated at 4 dpi ( Figure 2G ) (Chatterjee et al, 2020; Crouch, 2000; Oczypok et al, 2017; Prabhakaran et al, 2003). Collectively, our data show that SARS-CoV2 infection in GSH results in high viral load at the onset of infection that is characterized by lung injury and inflammation.…”

Host genome analysis of structural variations by Optical Genome Mapping provides clinically valuable insights into genes implicated in critical immune, viral infection, and viral replication pathways in patients with severe COVID-19

“…The ∼248.1 kb heterozygous inversion disrupting the MUC4 gene identified in five patients suggests it as a candidate to play a role in increasing disease severity. The mucins have been found to play a critical role in host defense against several respiratory pathogens that include pseudomonas aeruginosa (PA), respiratory syncytial virus (RSV), influenza viruses, and SARS-CoV-2 [ 72, 73 ]. Respiratory mucous functions as the primary barrier against the inhaled pathogen(s) [ 75 ].…”

Early humoral defence: Contributing to confining COVID‐19 to conducting airways?

“…The experimental opportunities may explain the extreme imbalance between mucus research and plasma exudation research (not lending itself to in vitro nor mouse in vivo approaches). Typically, airway mucus reviews entirely fail to even mention plasma exudation, 67,68 so even reviews focused on mucus defence in COVID-19. 67 Mucus may have some barrier functions 68 conceivably attenuating both airway absorption and exudation of molecules.…”

“…Typically, airway mucus reviews entirely fail to even mention plasma exudation, 67,68 so even reviews focused on mucus defence in COVID-19. 67 Mucus may have some barrier functions 68 conceivably attenuating both airway absorption and exudation of molecules. However, occurrence of mucus in human airways evidently has not prevented successful sampling of large plasma proteins by gentle lavage procedures-if the largest plasma proteins appear at even greater concentrations close to the epithelial apex in tethered airway secretions, that may give rise to speculations of added defence efficacy including opportunities for mucus-plasma interactions.…”