HUMAN DPP4/CD26 TRANSGENIC MICE AS SURROGATE MODELS FOR MERS

Abstract

Continued occurrences of the Middle East Respiratory Syndrome caused by a coronavirus (MERS-CoV) and its proven transmissibility among humans constitute an ongoing public health threat. Animal models, especially small animal models that simulate human disease are needed for studies of pathogenesis and development of vaccines and antivirals for prevention and treatment of MERS-CoV infection and disease. Mice and other commonly used laboratory small animal species (i.e., hamsters and ferrets) are not susceptible to MERS-CoV because they lack the expression of human dipeptidyl peptidase 4 (hDPP4), the functional viral entry receptor. To overcome this deficiency, we developed several lineages of transgenic (Tg) mice expressing hDPP4 globally by using the pCAGGS.MCS under the control of the CAG promoter, which is a composite promoter consisting of the cytomegalovirus (CMV)/immediate-early enhancer and the chicken β-actin promoter, containing rabbit globin splicing and polyadenylation sites, as surrogate models for MERS-CoV infections. We showed that one lineage (line 52) of Tg mice globally expressing hDPP4 is highly susceptible to intranasal (i.n.) challenge with a high-dose (i.e., 106 50% tissue culture infectious dose [TCID50]) of MERS-CoV, resulting in acute death, by day 6, profound weigh loss (> 20%) starting at day 2, acute and intense viral infection in lungs with prominent inflammatory infiltrates and prominent viral infection at day 4 in the brain with little to no cellular infiltrates. Additionally, studies identified the 50% lethal dose (LD50) and the 50% infectious dose (ID50) of MERS-CoV to be ~5 and 0.4 TCID50 of MERS-CoV, respectively. This Tg mouse model has been used successfully as a robust preclinical model for testing the efficacy of medical countermeasures for MERS.