Date Published: August 21, 2014
Publisher: Public Library of Science
Author(s): Darryl Falzarano, Emmie de Wit, Friederike Feldmann, Angela L. Rasmussen, Atsushi Okumura, Xinxia Peng, Matthew J. Thomas, Neeltje van Doremalen, Elaine Haddock, Lee Nagy, Rachel LaCasse, Tingting Liu, Jiang Zhu, Jason S. McLellan, Dana P. Scott, Michael G. Katze, Heinz Feldmann, Vincent J. Munster, Mark R. Denison.
The availability of a robust disease model is essential for the development of countermeasures for Middle East respiratory syndrome coronavirus (MERS-CoV). While a rhesus macaque model of MERS-CoV has been established, the lack of uniform, severe disease in this model complicates the analysis of countermeasure studies. Modeling of the interaction between the MERS-CoV spike glycoprotein and its receptor dipeptidyl peptidase 4 predicted comparable interaction energies in common marmosets and humans. The suitability of the marmoset as a MERS-CoV model was tested by inoculation via combined intratracheal, intranasal, oral and ocular routes. Most of the marmosets developed a progressive severe pneumonia leading to euthanasia of some animals. Extensive lesions were evident in the lungs of all animals necropsied at different time points post inoculation. Some animals were also viremic; high viral loads were detected in the lungs of all infected animals, and total RNAseq demonstrated the induction of immune and inflammatory pathways. This is the first description of a severe, partially lethal, disease model of MERS-CoV, and as such will have a major impact on the ability to assess the efficacy of vaccines and treatment strategies as well as allowing more detailed pathogenesis studies.
Since the emergence of MERS-CoV in 2012, researchers have worked to establish animal disease models to study the pathogenesis of this virus and to develop effective countermeasures. With over 836 cases and at least 290 deaths , there has been a rapid increase in the number of MERS-CoV cases as diagnostics are being more widely applied. While dromedary camels are suspected to be involved in zoonotic transmission of MERS-CoV –; and camel as well as horse DPP4 can efficiently facilitate virus entry , the mechanism(s) by which most people acquire MERS-CoV is still unclear. Since targeted attempts to prevent zoonotic transmission are currently not feasible and significant morbidity and mortality still occur in individuals with comorbidities, developing effective prophylactic and therapeutic treatment strategies remains a high priority. Although several treatment regimens have been suggested for use in patients based on in vitro MERS-CoV studies or treatment implemented during the SARS-CoV pandemic, only one such treatment has been tested in vivo against MERS-CoV to date . To enable a better evaluation of MERS-CoV treatment and prevention strategies, an animal model more representative of severe human disease is crucial.
In MERS-CoV-infected common marmosets, clinical disease was more severe than in the rhesus macaque, was of longer duration and resulted in euthanasia of some animals. Viral loads in the lungs were up to 1000 times higher than those in the rhesus macaque lungs (mean viral load in the lungs 1.2×103 in rhesus vs. 1.5×106 in marmosets on 3 dpi; 6.8×102 in rhesus vs. 2.1×106 in marmosets on 6 dpi) . Two of the six animals that were not euthanized at the scheduled 3 dpi necropsy had to be euthanized due to severity of disease, making this the first lethal MERS-CoV animal model. In both the marmoset and rhesus macaque  models, viral replication occurred predominantly in the lower respiratory tract; however, in marmosets MERS-CoV RNA was also detected in the blood. This is suggestive of a more systemic dissemination that was corroborated by the detection of viral RNA in nearly all tested tissues in all infected animals. Taken together, the data from the common marmoset model suggest that this model more closely recapitulates severe, even lethal, human disease caused by MERS-CoV. This differs from the rhesus macaque model for MERS-CoV –, which more closely resembles mild to moderate human disease.