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

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) was initially isolated from a Saudi Arabian man with fatal pneumonia. Since the original case in 2012, MERS-CoV infections have been reported in >1500 humans, and the case fatality rate is currently 35%. This lineage C betacoronavirus has been reported to cause a wide range of disease severity in humans, ranging from asymptomatic to progressive fatal pneumonia that may be accompanied by renal or multiorgan failure. Although the clinical presentation of human MERS-CoV infection has been documented, many facets of this emerging disease are still unknown and could be studied with animal models. Several animal models of MERS-CoV have been developed, including New Zealand white rabbits, transduced or transgenic mice that express human dipeptidyl peptidase 4, rhesus macaques, and common marmosets. This review provides an overview of the current state of knowledge on human MERS-CoV infections, the probable origin of MERS-CoV, and the available animal models of MERS-CoV infection. Evaluation of the benefits and limitations of these models will aid in appropriate model selection for studying viral pathogenesis and transmission, as well as for testing vaccines and antivirals against MERS-CoV.Keywords animal models, common marmosets, dipeptidyl peptidase 4, mice, Middle East respiratory syndrome coronavirus, pathogenicity, rabbits, respiratory system, review, rhesus macaques, transgenic Middle East respiratory syndrome coronavirus (MERS-CoV) was first isolated from a man in Saudi Arabia in 2012, and MERS-CoV infections have now been reported in >20 countries. 76,79 Originally called human coronavirus-EMC/2012, the virus was renamed MERS-CoV by the International Committee on Taxonomy of Viruses. 20,67 In humans, MERS-CoV is 1 of 6 coronaviruses that cause respiratory disease; however, it is currently the only known pathogenic human lineage C betacoronavirus. 31,68 MERS-CoV infections in humans range from asymptomatic to progressive fatal pneumonia with occasional renal or multiorgan failure. 44,52 To date, published autopsy data from fatal human cases are not available, and the exact route of viral transmission to and among humans is unknown. Additionally, there are currently no approved MERS-CoV-specific countermeasures. Thus, development of animal models to study the pathology and pathogenesis of MERS-CoV, the routes of viral transmission, and the efficacy of treatments and vaccines is critical. Here, we review the current state of knowledge on MERS-CoV infections in humans and potential animal reservoirs for the virus and provide an overview and analysis of animal models of MERS-CoV infection.

Development of Medical Countermeasures to Middle East Respiratory Syndrome Coronavirus

“…Studies in mice, both dipeptidyl peptidase-4 (dipeptidyl peptidase-4 or cluster differentiation 26) transduced and transgenic, and in rabbits, hamsters, and ferrets have been reviewed elsewhere ( 16 , 20 , 21 ). These small animal models have been used for screening potential MERS-CoV medical countermeasures ( 13 , 14 , 22 ).…”

Domestic Pig Unlikely Reservoir for MERS-CoV

“…Our current understanding of the pathogenesis of MERS-CoV is therefore mostly based on data derived from studies in animal models. Although the first animal model used to study MERS-CoV pathogenesis and test potential countermeasures became available shortly after the discovery of MERS-CoV ( 3 ), all the animal models that have been developed so far have drawbacks ( 4 ). Because of the host restriction conferred by the binding of the MERS-CoV spike protein to its receptor, dipeptidyl peptidase 4 (DPP4), small animal models that are routinely used to conduct infectious disease research are not naturally susceptible to MERS-CoV infection.…”

Modeling Emergent Diseases

“…8 Evidence suggests dromedary camels may be a relevant zoonotic reservoir for human exposure through routine handling, husbandry and food sources (eg, milk, meat); however, bats and/or other animals may also serve as possible reservoirs for the virus. 1,2,17 In this issue of Veterinary Pathology, Baseler and colleagues review the breadth of recently developed animal models to study MERS-CoV infection. 2 The authors highlight the advantages of the different models and compare their specific relevance for study of MERS-CoV.…”

“…1,2,17 In this issue of Veterinary Pathology, Baseler and colleagues review the breadth of recently developed animal models to study MERS-CoV infection. 2 The authors highlight the advantages of the different models and compare their specific relevance for study of MERS-CoV. From this review, several important considerations can be made regarding outbreaks of emergent diseases.…”

“…6,16 As pointed out Baseler et al, only a subset of the animal models had an experimental phenotype that sufficiently replicated human disease, but these results could not have been predicted prior to methodical testing and validation. 2 Alternatively, recent studies have identified SARS-like coronaviruses circulating in bats that have potential for future emergence in humans. 10 Could testing of these viruses in animal models provide a novel and proactive approach that provides information relevant to rapid investigation and control of future viral zoonoses?…”