175: Interleukin-13 predisposes mice to more severe influenza infection by suppressing interferon responses and activating microRNA-21/PI3K
Rationale: Asthmatics and COPD patients are more susceptible to viral infections, which in turn are a major cause of exacerbations. However, the immunological mechanisms underpinning this association are largely unknown. Anti-interleukin (IL)-13 is currently in clinical trials for asthma, but the role of this cytokine in predispositing to viral infections is unknown. Methods: BALB/c mice were subjected to Ovalbumin (Ova)-, house dust mite (HDM)- or recombinant IL-13 (rIL-13)-induced models of allergic airway disease (AAD), or cigarette smoke-induced COPD, and infected with influenza virus (A/PR/8/34 strain). Some groups were treated with anti-IL-13 neutralizing antibody, miRNA-21-specific anatgomirs or PI3K inhibitors during influenza infection. The effects of infection on hallmark features of AAD (airway hyper-responsiveness [AHR], mucus secreting cell [MSC] numbers and eosinophil infiltration), COPD (lung function, inflammation) and on antiviral responses (viral load and interferon [IFN]-α, -β, -λ, -γ levels) were assessed. The cellular source of IL-13 was determined using novel IL-13 reporter mice. Results: Influenza infection increased the severity of Ova-, HDM- and rIL-13-induced AAD by increasing AHR, MSC numbers and lung eosinophils. Importantly, anti-IL-13 treatment during AAD returned AHR, MSC numbers and eosinophils back to control levels. Infection also exacerbated COPD. All models resulted in increased viral load, which correlated with suppressed IFN-α, -β, -λ, -γ and increased miR-21 and PI3K levels in the lung. Anti-IL-13 treatment also improved anti-viral responses leading to reduced viral load. IL-13 increased both miRNA-21 and PI3K. Inhibition of these molecules protected against infection. Influenza infection increased IL-13-production by NKT cells, ILC2s and Th2 cells. Conclusion: IL-13 responses during AAD and COPD lead to impaired antiviral immune responses resulting in more severe influenza infection that exacerbated the underlying disease. These studies identify anti-IL-13 and miRNA-21 and PI3K inhibitors as a potential therapies in influenza infections and influenza-induced exacerbations.