Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice

Significance Middle East respiratory syndrome, caused by a zoonotically transmitted coronavirus (MERS-CoV), has a high mortality (∼36%). Because of limited autopsy data on tissues from MERS fatalities, a small animal model can provide an important tool to better understand the disease. We humanized the mouse locus of the virus receptor DPP4, preserving native DPP4 expression. After inoculating hDPP4 knockin mice with MERS-CoV, there was virus replication without disease. We then generated a mouse-adapted MERS-CoV by serial passage in hDPP4 knockin mice. The resultant virus causes fatal lung disease that includes diffuse alveolar damage and immune dysregulation. Here, we characterize the pathologic features of the model and elucidate key aspects of the immunopathology and factors contributing to virulence.