Influenza A Induces the Major Secreted Airway Mucin MUC5AC in a Protease–EGFR–Extracellular Regulated Kinase–Sp1–Dependent Pathway

Abstract

Mucins, the main glycoproteins present within mucus, modulate the rheologic properties of airways and participate in lung defense. They are thought to be able to trap and eliminate microorganisms from the lung. Among the mucins secreted in the lung, MUC5AC is the most prominent factor secreted by surface epithelial cells. Although much is known about the signaling pathways involved in the regulation of MUC5AC by host factors such as cytokines or proteases, less is known about the pathways triggered by microorganisms and, specifically, by influenza A virus (IAV). We therefore set up experiments to dissect the molecular mechanisms responsible for the potential modulation of MUC5AC by IAV. Using epithelial cells, C57/Bl6 mice, and IAV strains, we measured MUC5AC expression at the RNA and protein levels, specificity protein 1 (Sp1) activation, and protease activity. Intermediate molecular partners were confirmed using pharmacological inhibitors, blocking antibodies, and small interfering (si)RNAs. We showed in vitro and in vivo that IAV up-regulates epithelial cell-derived MUC5AC and Muc5ac expression in mice, both at transcriptional (through the induction of Sp1) and translational levels. In addition, we determined that this induction was dependent on a protease-epithelial growth factor receptor-extracellular regulated kinase-Sp1 signaling cascade, involving in particular the human airway trypsin. Our data point to MUC5AC as a potential modulatory mechanism by which the lung epithelia respond to IAV infection, and we dissect, for the first time to the best of our knowledge, the molecular partners involved. Future experiments using MUC5AC-targeted strategies should help further unravel the pathophysiological consequences of IAV-induced MUC5AC expression for lung homeostasis.

Influenza Promotes Pneumococcal Growth during Coinfection by Providing Host Sialylated Substrates as a Nutrient Source

“…We found that transcription of Muc5ac was upregulated in the nasopharynx during influenza infection as part of the inflammatory response, consistent with a previous report in the lungs of influenza-infected mice (Barbier et al, 2012). We also found that mucus and Muc5ac secretion increased during influenza infection, and that reducing mucins by genetic knockout of Muc5ac , or solubilizing mucus by N-acetylcysteine treatment decreased influenza-induced pneumococcal growth.…”

Human Dendritic Cell Response Signatures Distinguish 1918, Pandemic, and Seasonal H1N1 Influenza Viruses

“…The gene for transcription factor SP1 was identified by upstream regulatory analysis of the 1918 specific cluster. The induction of SP1 in epithelial cells has been linked to exacerbated responses to IAV infection (60). This association and the presence of inflammatory genes in the 1918-specific cluster are interesting in view of the early and high levels of inflammation associated with 1918 infection in in vivo models (61).…”

Streptococcus pneumoniae: transmission, colonization and invasion

“…IAV-induced inflammation stimulates both the expression of mucin glycoproteins and the flow of mucus 10,11 . There are more pneumococci in nasal secretions of pups with IAV co-infection (Fig.…”