Characterization and demonstration of the value of a lethal mouse model of Middle East respiratory syndrome coronavirus infection and disease

Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID₅₀) and lethal dose (LD₅₀) of virus were estimated to be < 1 and 10 TCID₅₀ of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID₅₀/LD₅₀ determinations, and all were fully immune to challenge with 100 LD₅₀ of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD₅₀ of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 10⁵ LD₅₀ of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research.