Infection with MERS-CoV Causes Lethal Pneumonia in the Common Marmoset

Falzarano, Darryl; Wit, Emmie de; Feldmann, Friederike; Rasmussen, Angela L.; Okumura, Atsushi; Peng, Xinxia; Thomas, Matthew; Doremalen, Neeltje van; Haddock, Elaine; Nagy, Lee; LaCasse, Rachel; Liu, Tingting; Zhu, Jiang; McLellan, Jason S.; Scott, Dana; Katze, Michael G.; Feldmann, Heinz; Munster, Vincent J.

doi:10.1371/journal.ppat.1004250

Cited by 196 publications

(286 citation statements)

References 41 publications

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“…25 Clinical signs included tachypnea, labored or shallow breathing, cyanosis, and hemorrhagic oral discharge, which necessitated early euthanasia of 2 of 9 marmosets. Clinical signs were first noted 1 dpi, peaked at 4 to 6 dpi, and resolved by 13 dpi.…”

Section: Common Marmosetsmentioning

confidence: 99%

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

2016

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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.

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Section: Common Marmosetsmentioning

confidence: 99%

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

2016

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“…Analysis of the DPP4 gene tree shows no clear phylogenetic clustering of permissive and nonpermissive hosts (Figure 5; see also 49). In Figure 5, blue indicates permissive hosts and red indicates nonpermissive hosts (58)(59)(60)(61)(62)(63)(64)(81)(82)(83)(84). The lack of a clear pattern of permissivity among closely related DPP4 genes suggests that other aspects of DPP4 may be more important than the linear amino acid sequence, such as structural similarity or conservation of posttranslational modifications (e.g., glycosylation).…”

Section: Evolutionary Implications Of Virus-host Cell Receptor Interamentioning

confidence: 99%

Coronavirus Host Range Expansion and Middle East Respiratory Syndrome Coronavirus Emergence: Biochemical Mechanisms and Evolutionary Perspectives

Peck¹,

Burch²,

Heise

et al. 2015

Annu. Rev. Virol.

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Coronaviruses have frequently expanded their host range in recent history, with two events resulting in severe disease outbreaks in human populations. Severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in 2003 in Southeast Asia and rapidly spread around the world before it was controlled by public health intervention strategies. The 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak represents another prime example of virus emergence from a zoonotic reservoir. Here, we review the current knowledge of coronavirus cross-species transmission, with particular focus on MERS-CoV. MERS-CoV is still circulating in the human population, and the mechanisms governing its cross-species transmission have been only partially elucidated, highlighting a need for further investigation. We discuss biochemical determinants mediating MERS-CoV host cell permissivity, including virus spike interactions with the MERS-CoV cell surface receptor dipeptidyl peptidase 4 (DPP4), and evolutionary mechanisms that may facilitate host range expansion, including recombination, mutator alleles, and mutational robustness. Understanding these mechanisms can help us better recognize the threat of emergence for currently circulating zoonotic strains.

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“…Furthermore, experimental immunogens can elicit an anti-MERS-CoV response (19,20). However, no MERS-CoV targeting therapeutic has been demonstrated to function in vivo, partly because of limited small animal models of infection (21)(22)(23). MERS-CoV does not natively replicate in wild-type mice.…”

mentioning

confidence: 99%

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

Pascal

Coleman

Mujica

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

203

255

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Traditional approaches to antimicrobial drug development are poorly suited to combatting the emergence of novel pathogens. Additionally, the lack of small animal models for these infections hinders the in vivo testing of potential therapeutics. Here we demonstrate the use of the VelocImmune technology (a mouse that expresses human antibody-variable heavy chains and κ light chains) alongside the VelociGene technology (which allows for rapid engineering of the mouse genome) to quickly develop and evaluate antibodies against an emerging viral disease. Specifically, we show the rapid generation of fully human neutralizing antibodies against the recently emerged Middle East Respiratory Syndrome coronavirus (MERS-CoV) and development of a humanized mouse model for MERS-CoV infection, which was used to demonstrate the therapeutic efficacy of the isolated antibodies. The VelocImmune and VelociGene technologies are powerful platforms that can be used to rapidly respond to emerging epidemics.

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Infection with MERS-CoV Causes Lethal Pneumonia in the Common Marmoset

Cited by 196 publications

References 41 publications

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

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

Coronavirus Host Range Expansion and Middle East Respiratory Syndrome Coronavirus Emergence: Biochemical Mechanisms and Evolutionary Perspectives

Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection

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