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

Aran Singanayagam; Joseph Footitt; Benjamin T Kasdorf; Matthias Marczynski; Michael T Cross; Lydia J Finney; Maria-Belen Trujillo Torralbo; Maria Calderazzo; Jie Zhu; Julia Aniscenko; Thomas B Clarke; Philip L Molyneaux; Nathan W Bartlett; Miriam F Moffatt; William O Cookson; Jadwiga Wedzicha; Christopher M Evans; Oliver Lieleg; Patrick Mallia; Sebastian L Johnston

We show here, that MUC5AC is selectively induced during virus-induced COPD exacerbations and increased compared to virus-infected healthy subjects. By contrast, MUC5B was not induced above baseline and did not differ between COPD and control subjects at any timepoint, indicating that MUC5AC is the major induced mucin during exacerbations. We also found positive correlations between MUC5AC and a range of inflammatory markers. Since airway inflammation is enhanced in COPD exacerbations and believed to contribute to duration and severity of RV induced illnesses 17, 18 we also determined the relationship between MUC5AC and exacerbation severity, finding positive correlations with virus loads, symptom scores and acute lung function decline. MUC5AC is one of the major glycoprotein components of airway mucus and it is therefore unsurprising that its expression during virus infection correlates with lower respiratory symptom scores which comprise an assessment of sputum production. The correlation of MUC5AC with PEF decline can be explained by the fact that greater mucus production is likely to contribute directly to airway obstruction during exacerbation. Our findings in this acute human infection model are in keeping with clinical studies that have reported the association of symptomdefined chronic mucus hypersecretion phenotype with airflow limitation and FEV 1 decline 19, 25 and an animal study showing that genetic deletion of Muc5ac reduces mucus occlusion and improves lung function in models of allergic airway inflammation 11 .