184: Glucocorticosteroids dampen anti-viral defences and enhance the replication of respiratory viruses

Aims Viral upper respiratory tract infections caused by rhinovirus (RV) and influenza A virus (IAV) are associated with 50–80% of asthma exacerbations. Inhaled glucocorticosteroids (GCS) are routinely used to relieve asthma symptoms, and while it has been widely reported that GCS reduce inflammation associated with viral infection, the effects of GCS on viral replication has not been comprehensively examined. Methods Using primary human airway cells and a mouse model of IAV infection we examined the effect of GCS on the production of inflammatory mediators, anti-viral responses and viral replication following RV and/or IAV infection. Results GCS pre-treatment of epithelial cells significantly reduced IL-8, IL-6 and IP-10 production following RV and IAV infection, compared to untreated controls. The expression of anti-viral genes, including ISG56, ISG15, viperin and MxA, were significantly reduced in epithelial cells, fibroblasts and macrophages pre-treated with GCS prior to infection with RV or IAV. The impairment of anti-viral responses observed following GCS pre-treatment was associated with enhanced RV and IAV replication in both epithelial cells and fibroblasts. GCS pre-treatment of mice prior to IAV infection was associated with significant weight loss and severe disease progression compared with untreated mice. Viral loads were significantly elevated in both the lungs and nasal tissues of the GCS treated mice, and there were significantly elevated levels of IL-6, MCP-1 and KC in BAL fluid. Interferon and anti-viral ISG expression were significantly reduced in GCS treated mice. Treatment with recombinant interferon after infection delayed the onset of disease and improved survival. Conclusions Our data indicate that GCS at therapeutic doses enhanced virus replication through the suppression of innate anti-viral responses. Interferon treatment improved disease severity in the mouse model, suggesting this may be a viable therapeutic option to counteract the adverse effects of GCS treatment on viral replication and innate immune suppression.