Rapid generation of a mouse model for Middle East respiratory syndrome

Abstract

In this era of continued emergence of zoonotic virus infections, the rapid development of rodent models represents a critical barrier to public health preparedness, including the testing of antivirus therapy and vaccines. The Middle East respiratory syndrome coronavirus (MERS-CoV) was recently identified as the causative agent of a severe pneumonia. Given the ability of coronavirus to rapidly adapt to new hosts, a major public health concern is that MERS-CoV will further adapt to replication in humans, triggering a pandemic. No small-animal model for this infection is currently available, but studies suggest that virus entry factors can confer virus susceptibility. Here, we show that mice were sensitized to MERS-CoV infection by prior transduction with adenoviral vectors expressing the human host-cell receptor dipeptidyl peptidase 4. Mice developed a pneumonia characterized by extensive inflammatorycell infiltration with virus clearance occurring 6-8 d after infection. Clinical disease and histopathological changes were more severe in the absence of type-I IFN signaling whereas the T-cell response was required for virus clearance. Using these mice, we demonstrated the efficacy of a therapeutic intervention (poly I:C) and a potential vaccine [Venezuelan equine encephalitis replicon particles expressing MERS-CoV spike protein]. We also found little protective cross-reactivity between MERS-CoV and the severe acute respiratory syndrome-CoV. Our results demonstrate that this system will be useful for MERS-CoV studies and for the rapid development of relevant animal models for emerging respiratory viral infections.emerging pathogen | interferon | SARS

A Comparative Review of Animal Models of Middle East Respiratory Syndrome Coronavirus Infection

“…In the first model, an adenoviral vector was used to induce transient expression of hDPP4 in the lungs of BALB/c mice (National Cancer Institute, Frederick, MD, USA), C57BL/6 mice (National Cancer Institute), and multiple knockout mouse strains. 80 hDPP4 was expressed only by epithelial cells lining the airways and alveoli. After intranasal inoculation with MERS-CoV, clinical signs in the hDPP4-transduced wild-type mice were minimal and characterized by lack of weight gain in young mice and mild weight loss in older mice.…”

Mapping the Specific Amino Acid Residues That Make Hamster DPP4 Functional as a Receptor for Middle East Respiratory Syndrome Coronavirus

“…Nonhuman primates (NHPs) (2-4) and dromedary camels (5) are naturally susceptible. In addition, several mouse models have been developed, and expression of the human variant of the receptor of MERS-CoV, dipeptidyl peptidase 4 (DPP4), in mice allows viral replication (6)(7)(8).No other small-animal models have been developed. Therefore, if a treatment against MERS-CoV is shown to be successful in the mouse model, further characterization of the treatment needs to be performed in NHPs, a relatively expensive animal model to which access is limited.…”

Middle East Respiratory Syndrome

“…In one study, mice were sensitized to MERS-CoV infection using an adenovirus expressing human DPP4 (hDPP4) 35 . An advantage of this approach is that any strain of mouse can be made susceptible to MERS-CoV.…”