Searching for animal models and potential target species for emerging pathogens: Experience gained from Middle East respiratory syndrome (MERS) coronavirus

Vergara-Alert, Júlia; Vidal, Enric; Bensaid, Albert; Segalés, Joaquim

After the identification of MERS-CoV in 2012 [6] , the efforts were directed to develop an animal model to study pathogenesis and to test the efficacy of vaccines and/or treatments in vivo. Similar to SARS-CoV, rhesus macaques have demonstrated susceptibility to MERS-CoV [21] [22] [23] . A work led by Munster demonstrated that the common marmoset is also suitable as a MERS-CoV model [24] . They showed that this model recapitulates the disease observed in humans; therefore, findings in the evaluation of potential therapeutic strategies might be implemented in humans. However, small animals are required for controlled, large and comprehensive studies. While, at first, experiences with SARS-CoV turned out to be very helpful for the research on MERS-CoV, the development of a small animal model for MERS was a more difficult task [18, 19] . Raj and collaborators rapidly identified dipeptidyl peptidase-4 (DPP4) as the functional receptor for MERS-CoV [25] , and DPP4 is present in lung cells of many rodents. Thus, rodents were expected to be susceptible for MERS-CoV. However, and as predicted by the crystal structure analysis of the MERS-CoV receptor binding domain (RBD) with the human DPP4 (hDDP4) extracellular domain [26] , so far, no rodent model is naturally permissive for MERS-CoV infection. In Syrian hamster, the DPP4 receptor was shown to be expressed on bronchiolar epithelium, but inoculation of MERS-CoV via aerosols or intratracheal routes with different doses did not lead to productive infection [27] . Wild type and immune-deficient mice were also tested for MERS-CoV infection without success [28] . Since then, several groups have been focused on new strategies to develop a small animal model susceptible to MERS-CoV infection. It was found that mouse cells could be made permissive for MERS-CoV when expressing hDPP4. Consequently, the hDPP4 was transduced into mouse lungs using an adenovirus vector, which resulted in animals susceptible to MERS-CoV infection. These mice exhibited pneumonia and extensive inflammatory-cell infiltration with the presence of virus in the lungs [29] . Recently, a transgenic mice model expressing hDPP4, highly susceptible to MERS-CoV infection and able to display systemic lesions, has been developed [30] . As demonstrated for several diseases, transgenic animal models have become an important tool to improve medical research [31] . On the other hand, glycosylation of the murine DPP4 is a major factor impacting the receptor function by blocking the binding to MERS-CoV [32] . Therefore, the modification of the mouse genome to match the sequence in the hDPP4 made this species susceptible to MERS-CoV infection [33] . Accordingly, these newly established mice models are useful to evaluate the efficacy of vaccines and therapeutic agents against MERS-CoV infection [30, [34] [35] [36] . VelocImmune and VelociGene technologies have been used to develop a humanized mouse model for MERS-CoV infection [36] ; these methodologies can be also applied for other pathogens in future emerging epidemics.