Relative timing of type I interferon response and virus replication determines disease outcome during MERS-CoV infection

Type 1 interferons (IFN-I) generally protect mammalian hosts from virus infections, but in some cases, IFN-I is pathogenic. Because IFN-I is protective, it is commonly used to treat virus infections for which no specific approved drug or vaccine is available. The Middle East respiratory syndrome-coronavirus (MERS-CoV) is such an infection, yet little is known about the role of IFN-I in this setting. Here we show that IFN-I signaling is protective during MERS-CoV infection. Blocking IFN-I signaling resulted in delayed virus clearance, enhanced neutrophil infiltration and impaired MERS-CoV-specific T cell responses. Notably, IFN-I administration within 1-day post infection (before virus titers peak) protected mice from lethal infection, despite a decrease in ISG (interferon stimulated gene) and inflammatory cytokine gene expression. In contrast, delayed IFN-I treatment failed to effectively inhibit virus replication, increased infiltration and activation of monocyte-macrophages and neutrophils into the lungs and enhanced pro-inflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sub-lethal infection. Together, these results suggest that the relative timing of the IFN-I response and maximal virus replication is key in determining outcomes, at least in infected mice. By extension, IFN-I or combination therapy may need to be used cautiously to treat virus infections in clinical settings. Examination of gene expression in early and late IFN treated lungs after MERS-CoV infection.