Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4

Li, Kun; Wohlford‐Lenane, Christine L.; Perlman, Stanley; Zhao, Jincun; Jewell, Alexander K.; Reznikov, Leah R.; Gibson‐Corley, Katherine N.; Meyerholz, David K.; McCray, Paul B.

doi:10.1093/infdis/jiv499

Cited by 425 publications

(491 citation statements)

References 47 publications

Supporting

Mentioning

458

Contrasting

Unclassified

Order By: Relevance

“…Generation of transgenic mice expressing a virus receptor is a common strategy to make mice permissive to infection. Several groups in addition to ours developed mice with transgenic expression of hDPP4 using different promoters [25][26][27][28]. The disease severity following MERS-CoV infection in transgenic mice correlated with the cellular distribution and expression level of hDPP4.…”

Section: Introductionmentioning

confidence: 95%

“…The disease severity following MERS-CoV infection in transgenic mice correlated with the cellular distribution and expression level of hDPP4. In transgenic mice expressing hDPP4 driven by the cytokeratin 18 promoter [26] or a ubiquitous promoter [25,27,28], MERS-CoV replicates and causes respiratory disease and mortality. However, the lethality was found to be secondary to overwhelming central nervous system (CNS) disease or multiorgan damage.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development of a Mouse-Adapted MERS Coronavirus

McCray

2019

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

First identified in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that can cause acute respiratory distress syndrome (ARDS), multiorgan failure, and death, with a case fatality rate of~35%. An animal model that supports MERS-CoV infection and causes severe lung disease is useful to study pathogenesis and evaluate therapies and vaccines. The murine dipeptidyl peptidase 4 (Dpp4) protein is not a functional receptor for MERS-CoV; thus, mice are resistant to MERS-CoV infection. We generated human DPP4 knock-in (hDPP4 KI) mice by replacing exons 10-12 at the mouse Dpp4 locus with exons 10-12 from the human DPP4 gene. The resultant human DPP4 KI mice are permissive to MERS-CoV (HCoV-EMC/2012 strain) infection but develop no disease. To generate a mouse model with associated morbidity and mortality from respiratory disease, we serially passaged HCoV-EMC/2012 strain in the lungs of young hDPP4 KI mice. After 30 in vivo passages, an adapted virus clone was isolated and designated MERS MA 6.1.2. This virus clone produced significantly higher titers than the parental clone in the lungs of hDPP4 KI mice and caused diffuse lung injury and a fatal respiratory infection. In this chapter, we will describe in detail the procedures used to mouse adapt MERS-CoV by serial passage of the virus in lungs. We also describe the methods used to isolate virus clones and characterize virus infection.

show abstract

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Development of a Mouse-Adapted MERS Coronavirus

McCray

2019

Methods in Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The other type of MERS-CoV-susceptible mice available to date includes knockin strains in which 3 or 13 exons of mouse DPP4 have been replaced with the homologous sequences from hDPP4 Li et al, 2016;Pascal et al, 2015). A major difference to the Tg mice described earlier is that the mouse-adapted MERS-CoV only produced disease in knockin mice after the virus has been passed 30 times in the knockin mouse (K. Li, P. McCray, and S. Perlman, 2016, personal communication), whereas the LD50 of MERS-CoV in these mice was around 10 4 pfu/ mouse.…”

Section: Animal Models For Cov Vaccine and Antivirals Studiesmentioning

confidence: 99%

Molecular Basis of Coronavirus Virulence and Vaccine Development

Enjuanes

Zúñiga

Castaño-Rodríguez

et al. 2016

Advances in Virus Research

149

141

View full text Add to dashboard Cite

Virus vaccines have to be immunogenic, sufficiently stable, safe, and suitable to induce long-lasting immunity. To meet these requirements, vaccine studies need to provide a comprehensive understanding of (i) the protective roles of antiviral B and T-cell-mediated immune responses, (ii) the complexity and plasticity of major viral antigens, and (iii) virus molecular biology and pathogenesis. There are many types of vaccines including subunit vaccines, whole-inactivated virus, vectored, and live-attenuated virus vaccines, each of which featuring specific advantages and limitations. While nonliving virus vaccines have clear advantages in being safe and stable, they may cause side effects and be less efficacious compared to live-attenuated virus vaccines. In most cases, the latter induce long-lasting immunity but they may require special safety measures to prevent reversion to highly virulent viruses following vaccination. The chapter summarizes the recent progress in the development of coronavirus (CoV) vaccines, focusing on two zoonotic CoVs, the severe acute respiratory syndrome CoV (SARS-CoV), and the Middle East respiratory syndrome CoV, both of which cause deadly disease and epidemics in humans. The development of attenuated virus vaccines to combat infections caused by highly pathogenic CoVs was largely based on the identification and characterization of viral virulence proteins that, for example, interfere with the innate and adaptive immune response or are involved in interactions with specific cell types, such as macrophages, dendritic and epithelial cells, and T lymphocytes, thereby modulating antiviral host responses and viral pathogenesis and potentially resulting in deleterious side effects following vaccination.

show abstract

“…Finally, a recent study has demonstrated that mice transgenic for hDPP4 under the epithelial-cell-specific promoters also support widespread MERS-CoV infection resulting in significant damage in the lungs and brain of infected mice (26). Although this model is improved relative to previously reported mouse models by limiting hDPP4 expression to epithelial cells, this is not coincident with the levels of expression and cell types in which endogenous mDPP4 is found.…”

mentioning

confidence: 94%

“…All three models of MERS-CoV infection in mice (22,25,26) have robust replication of MERS-CoV and, as such, have utility as a vehicle for testing of novel therapeutics or vaccines that inhibit MERS-CoV replication (25,26). However, they provide limited information about the natural pathogenesis of MERS-CoV infection in vivo (25).…”

mentioning

confidence: 99%

CD8 ⁺ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome

Coleman

Sisk

Halász

et al. 2017

J Virol

View full text Add to dashboard Cite

Middle East respiratory syndrome coronavirus (MERS-CoV) is an important emerging pathogen that was first described in 2012. While the cell surface receptor for MERS-CoV has been identified as dipeptidyl peptidase 4 (DPP4), the mouse DPP4 homologue does not allow virus entry into cells. Therefore, development of mouse models of MERS-CoV has been hampered by the fact that MERS-CoV does not replicate in commonly available mouse strains. We have previously described a mouse model in which mDPP4 was replaced with hDPP4 such that hDPP4 is expressed under the endogenous mDPP4 promoter. In this study, we used this mouse model to analyze the host response to MERS-CoV infection using immunological assays and transcriptome analysis. Depletion of CD4 ϩ T cells, CD8 ϩ T cells, or macrophages has no effect on MERS-CoV replication in the lungs of infected mice. However, we found that depletion of CD8 ϩ T cells protects and depletion of macrophages exacerbates MERS-CoV-induced pathology and clinical symptoms of disease. Overall, we demonstrate an important role for the inflammatory response in regulating MERS-CoV pathogenesis in vivo. IMPORTANCE The Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic respiratory virus that emerged from zoonotic sources in 2012. Human infections are still occurring throughout Saudi Arabia at a 38% case fatality rate, with the potential for worldwide spread via air travel. In this work, we identify the host response to the virus and identify inflammatory pathways and cell populations that are critical for protection from severe lung disease. By understanding the immune response to MERS-CoV we can develop targeted therapies to inhibit pathogenesis in the future. In vitro analysis of MERS-CoV and immune cells has suggested that MERS-CoV interacts with and infects T cells and macrophages. The receptor for MERS-CoV was identified as dipeptidyl peptidase 4 (DPP4) (4). T cells express DPP4, and DPP4 activity

show abstract

Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4

Cited by 425 publications

References 47 publications

Development of a Mouse-Adapted MERS Coronavirus

Development of a Mouse-Adapted MERS Coronavirus

Molecular Basis of Coronavirus Virulence and Vaccine Development

CD8 ⁺ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome

Contact Info

Product

Resources

About

Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4

Cited by 425 publications

References 47 publications

Development of a Mouse-Adapted MERS Coronavirus

Development of a Mouse-Adapted MERS Coronavirus

Molecular Basis of Coronavirus Virulence and Vaccine Development

CD8 + T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome

Contact Info

Product

Resources

About

CD8 ⁺ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome