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

Abstract 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.