Rapid generation of a mouse model for Middle East respiratory syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 13; pp. 4970 - 4975
• Main Authors: Zhao, Jincun, Li, Kun, Wohlford-Lenane, Christine, Agnihothram, Sudhakar S., Fett, Craig, Zhao, Jingxian, Gale, Michael J., Baric, Ralph S., Enjuanes, Luis, Gallagher, Tom, McCray, Paul B., Perlman, Stanley
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01-04-2014; National Acad Sciences
• Subjects: Animals; Antibodies; Antibodies, Viral - immunology; Biological Sciences; CD8-Positive T-Lymphocytes - virology; Cells; Coronavirus; Coronavirus - immunology; Coronavirus - physiology; Coronavirus Infections - immunology; Coronavirus Infections - prevention & control; Coronavirus Infections - virology; Cross Reactions - immunology; Disease Models, Animal; Genetic vectors; Humans; Infections; Interferon Type I - metabolism; Lungs; Mice; Mice, Inbred C57BL; Middle East; P values; Public health; Respiratory diseases; Respiratory Tract Infections - immunology; Respiratory Tract Infections - prevention & control; Respiratory Tract Infections - virology; Rodents; SARS virus; Severe Acute Respiratory Syndrome - immunology; Signal Transduction - immunology; T cell receptors; T lymphocytes; Viral infections; Viruses; Middle East; interferon; SARS; emerging pathogen
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1323279111

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 inflammatory-cell 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.