Type 1 IFNs (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 after infection (before virus titers peak) protected mice from lethal infection, despite a decrease in IFN-stimulated gene (ISG) and inflammatory cytokine gene expression. In contrast, delayed IFN-β treatment failed to effectively inhibit virus replication; increased infiltration and activation of monocytes, macrophages, and neutrophils in the lungs; and enhanced proinflammatory cytokine expression, resulting in fatal pneumonia in an otherwise sublethal 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-αβ or combination therapy may need to be used cautiously to treat viral infections in clinical settings.

Significance: Middle East respiratory syndrome coronavirus (MERS-CoV) can cause lethal pneumonia by infecting lung epithelial cells. Infection requires viral “spike” proteins, which catalyze virus–cell membrane fusion during cell entry. Fusion catalysis requires that spikes be first cleaved by cellular proteases. MERS-CoV spikes are cleaved in virus-producing cells before subsequent virus-cell entry, whereas other human coronaviruses have spikes that are cleaved in virus-infecting cells during virus-cell entry. Here, we found that the early MERS-CoV cleavages are required for the subsequent infection of human lung-like cells, but are dispensable for infection of several other cell types. Our findings demonstrate that the spike cleavage status of MERS-CoVs dictates cell tropism, and points to spike proteolytic processing as a correlate of MERS-CoV virulence.

In 2012, a zoonotic coronavirus was identified as the causative agent of Middle East respiratory syndrome and was named MERS coronavirus (MERS-CoV). As of August 11, 2016, the virus has infected 1,791 patients, with a mortality rate of 35.6%. Although MERS-CoV generally causes subclinical or mild disease, infection can result in serious outcomes, including acute respiratory distress syndrome and multi-organ failure in patients with comorbidities. The virus is endemic in camels in the Arabian Peninsula and Africa and thus poses a consistent threat of frequent reintroduction into human populations. Disease prevalence will increase substantially if the virus mutates to increase human-to-human transmissibility. No therapeutics or vaccines are approved for MERS; thus, development of novel therapies is needed. Further, since many MERS cases are acquired in healthcare settings, public health measures and scrupulous attention to infection control are required to prevent additional MERS outbreaks.