MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation

Abstract

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus that is rich in mucin glycoproteins. Disrupted mucus production is a cardinal feature of chronic respiratory diseases but how this alteration affect interactions between mucins and pathogens is complex and poorly understood. Here, we identify a central and unexpected role for the major airway mucin MUC5AC in pathogenesis of virus-induced exacerbations of chronic obstructive pulmonary disease (COPD). Virus induction of MUC5AC is augmented in COPD compared to healthy subjects, is enhanced in frequent exacerbators and correlates with inflammation, symptom severity and secondary bacterial infection during exacerbation. MUC5AC is functionally related to inflammation as MUC5ACdeficient (Muc5ac-/-) mice had attenuated rhinovirus-induced airway inflammation whilst exogenous MUC5AC glycoprotein administration augmented virus-induced inflammatory responses and bacterial load. Mechanistically, MUC5AC-augmentation of rhinovirus-induced inflammation occurred through release of extracellular adenosine triphosphate (ATP). Therapeutic suppression of virus-induced MUC5AC release using an epidermal growth factor receptor (EGFR) inhibitor ameliorated exaggerated pro-inflammatory responses in a mouse COPD exacerbation model. Collectively, these studies demonstrate previously unrecognised pro-inflammatory effects of MUC5AC during infection and thus highlight a key unforeseen role in driving COPD exacerbation severity.author/funder. All rights reserved. No reuse allowed without permission.

Bacterial and viral infections and related inflammatory responses in chronic obstructive pulmonary disease

“…The MUC5AC expression positively correlated with bronchial inflammation, virus load, secondary bacterial infections and clinical degree of COPD exacerbation. MUC5AC could exert its proinflammatory effect by stimulating epithelial cells to release extracellular adenosine triphosphate [ 101 ].…”

“…The MUC5AC expression positively correlated with bronchial inflammation, virus load, secondary bacterial infections and clinical degree of COPD exacerbation. MUC5AC could exert its proinflammatory effect by stimulating epithelial cells to release extracellular adenosine triphosphate[101].Respiratory viruses can increase the ability of some pathogens like S. aureus, S. pneumoniae and H. influentiae to adhere to lung epithelial cells by favoring the expression of adhesion molecules like fibronectin, ICAM-1 and platelet activating factor receptor[102]. Other proteins like influenza haemagglutinin and the RSV attachment glycoprotein (G) induced by respiratory viruses on the surface of the infected cells have a role in facilitating the adherence and internalization of pathogenic bacteria[103].…”

Genome-wide meta-analysis of pneumonia suggests a role for mucin biology and provides novel drug repurposing opportunities

“…This heavily glycosylated protein is lowly expressed in normal respiratory epithelium, however, is upregulated upon in response to perturbagens, such as viral infection 54,55 . We posit that upregulation of MUC5AC may be deleterious in the context of pneumonia given recent evidence that this protein can enhance airway inflammation induced by viral infection 56 , although dissection of the mechanisms of variants in this locus are warranted. Interestingly, there are some preliminary data that suggests MUC5AC is upregulated in the airway mucus of patients with severe COVID-19, although these studies were conducted using small sample sizes 57,58 .…”

Advances in chronic obstructive pulmonary disease: management of exacerbations

“…The importance of respiratory viruses has been highlighted by the 50% reduction in hospitalised exacerbations seen during the COVID-19 pandemic [7]: people shielding from coronavirus were also at less risk of acquiring rhinovirus. Airway infection drives airway inflammation and recent data suggest an important role for airway mucins [8] in the immunopathology of a COPD exacerbation. Accumulation of mucus and airway wall inflammation with associated bronchoconstriction increases the rate and work of breathing and leads to dynamic hyperinflation -a key mechanism driving breathlessness at a COPD exacerbation [9].…”