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

Singanayagam, A.; Footitt, J.; Kasdorf, B. T.; Marczynski, M.; Cross, M. T.; Finney, L. J.; Trujillo Torralbo, M.-B.; Calderazzo, M.; Zhu, J.; Aniscenko, J.; Clarke, T. B.; Molyneaux, P. L.; Bartlett, N. W.; Moffatt, M. F.; Cookson, W. O.; Wedzicha, J.; Evans, C. M.; Lieleg, O.; Mallia, P.; Johnston, S. L.

doi:10.1101/706804

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bioRxiv · 10.1101/706804

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

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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 MUC5AC-deficient (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.

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Singanayagam, A., Footitt, J., Kasdorf, B. T., Marczynski, M., Cross, M. T., Finney, L. J., Trujillo Torralbo, M.-B., Calderazzo, M., Zhu, J., Aniscenko, J., Clarke, T. B., Molyneaux, P. L., Bartlett, N. W., Moffatt, M. F., Cookson, W. O., Wedzicha, J., Evans, C. M., Lieleg, O., Mallia, P., Johnston, S. L.. 2019-07-22. MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation. https://doi.org/10.1101/706804

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