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 exacerbation symptoms such as cough, shortness of breath, chest tightness and wheezing, however they are only partially effective in preventing exacerbations, reducing the rate by only 40%. While it has been widely reported that GCS reduce inflammation associated with viral infection, the effects of GCS on viral infection itself has not been thoroughly examined. We hypothesised that the anti-inflammatory effects of GCS during asthma exacerbation may be offset by a detrimental effect of GCS on viral replication itself.
Firstly, we examined the effect of GCS on viral replication and the induction of innate immune responses following RV and IAV infection in vitro. Pre-treatment of primary human lung airway cells with GCS increased and prolonged viral replication of both RV and IAV. The induction of ISG56 and 2’5’OAS, markers of the innate anti-viral response, was significantly reduced in cells pre-treated with GCS prior to infection. GCS pre-treatment of primary human airway macrophages was also associated with inhibition of inflammatory mediator production and induction of antiviral genes in response to virus.
Secondly, we examined the effect of GCS on viral infection in vivo. Mice were pre-treated with GCS and infected with IAV. GCS treatment was associated with significantly elevated viral loads in the respiratory tract of mice and the induction of severe disease not observed in control mice. We are currently examining the effect of GCS on anti-viral responses in the lung of mice.
Our data indicate that GCS at therapeutic doses enhances virus replication through the suppression of innate anti-viral responses. The unintended detrimental consequence of GCS treatment on anti-viral defenses has potential implications for clinical practice.