Recurrent H1N1 Influenza A virus infections cause airway hyperinnervation and cough hypersensitivity via the IFN-γ–JAK–ERK1/2–CDK5 pathway

RATIONALE: Chronic cough patients present with increased airway sensory nerve density-a pathology often initiated by recurrent viral infections, notably H1N1. Infection-induced IFN-γ acts via its highly expressed receptors to promote neurite outgrowth in vitro. OBJECTIVES: To investigate the role of IFN-γ as a mediator in the development of airway hyperinnervation and cough hypersensitivity induced by recurrent H1N1 viral infections. METHODS: We studied the effects and underlying mechanisms of recurrent H1N1 viral infections on airway hyperinnervation and subsequent cough hypersensitivity. MEASUREMENTS AND MAIN RESULTS: Recurrent H1N1 viral infections in mice significantly enhanced cough sensitivity and airway inflammation, accompanied by elevated pulmonary IFN-γ + T cells/IFN-γ levels, vagal CDK5 activity, and airway nerve density. Anti-IFN-γ treatment abrogated these effects-cough hypersensitivity, IFN-γ + T cell infiltration, CDK5 upregulation, and airway hyperinnervation. Roscovitine treatment markedly attenuated viral infection-induced cough hypersensitivity, CDK5 activation in vagal ganglia, and airway hyperinnervation. Viral infections did not change gene expressions of IFN-γ receptors in vagal ganglia. Neither anti-IFN-γ nor roscovitine alleviated viral infection-induced airway inflammation. No evidence of airway hyperinnervation was observed following a single-dose H1N1 infection, either in the short term or long term. IFN-γ sensitized mouse vagal sensory neurons. Pharmacological inhibition of the JAK-ERK1/2-CDK5 pathways decreased IFN-γ-induced neurite outgrowth in mouse vagal sensory neurons. CONCLUSIONS: Recurrent H1N1 viral infections may cause airway hyperinnervation and cough hypersensitivity via the IFN-γ-JAK-ERK1/2-CDK5 pathways. Recurrent H1N1 viral infection-induced cough hypersensitivity may be mediated, in part, by IFN-γ-mediated airway hyperinnervation.