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 yet they are only partially effective. While it has been widely reported that GCS reduce inflammatory mediator production associated with viral infection, the effects of GCS on viral replication has not been comprehensively examined.
Using primary human airway cells we examined the effect of GCS on inflammatory mediator production, anti-viral responses and viral replication following RV and IAV infection. GCS pre-treatment of epithelial cells, fibroblasts and macrophages significantly reduced IL-8, IL-6 and IP-10 production following RV and IAV infection compared to untreated virus controls. The expression of anti-viral genes including ISG56, ISG15, viperin and MxA were significantly reduced in all 3 cell types following GCS pre-treatment prior to RV and IAV infection. 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.
Using a mouse model of IAV infection we identified that GCS pre-treatment prior to IAV infection was associated with significant weight loss and severe disease progression compared with untreated IAV infected mice. Viral loads were significantly elevated in both the lungs and nasal tissues of the GCS-treated mice, and IL-6, MCP-1 and KC levels were significantly elevated in bronchoalveolar lavage fluid. Interferon and anti-viral ISG expression were significantly reduced in the lungs of GCS-treated mice. Intranasal treatment with recombinant interferon 24 hrs following infection delayed the onset of disease and improved survival of mice treated with GCS.
Our findings indicate that GCS at therapeutic doses enhances virus replication through the suppression of innate anti-viral responses. Interferon treatment reduced disease severity in the mouse, suggesting this may be a viable therapeutic option to counteract the adverse effects of GCS treatment on viral replication and innate immune suppression in asthma patients.