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A mouse model for MERS coronavirus-induced acute respiratory distress syndrome

Nature Microbiology volume 2, Article number: 16226 (2017) Cite this article

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Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ARDS), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. Limited clinical studies indicate that humans infected with MERS-CoV exhibit pathology consistent with the late stages of ARDS, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. Models of MERS-CoV-induced severe respiratory disease have been difficult to achieve, and small-animal models traditionally used to investigate viral pathogenesis (mouse, hamster, guinea-pig and ferret) are naturally resistant to MERS-CoV. Therefore, we used CRISPR–Cas9 gene editing to modify the mouse genome to encode two amino acids (positions 288 and 330) that match the human sequence in the dipeptidyl peptidase 4 receptor, making mice susceptible to MERS-CoV infection and replication. Serial MERS-CoV passage in these engineered mice was then used to generate a mouse-adapted virus that replicated efficiently within the lungs and evoked symptoms indicative of severe ARDS, including decreased survival, extreme weight loss, decreased pulmonary function, pulmonary haemorrhage and pathological signs indicative of end-stage lung disease. Importantly, therapeutic countermeasures comprising MERS-CoV neutralizing antibody treatment or a MERS-CoV spike protein vaccine protected the engineered mice against MERS-CoV-induced ARDS.

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Figure 1: A CRISPR–Cas9 genetically engineered mouse model for MERS-CoV replication.
Figure 2: Mouse-adapted MERS-CoV causes fatal disease in 288/330+/+ mice.
Figure 3: Lung function in MERS-15-infected mice.
Figure 4: Clonal isolates of mouse-adapted MERS-CoV exhibit severe respiratory disease.
Figure 5: Human monoclonal antibody 3B11 protects mice from severe respiratory disease.
Figure 6: Vaccination of 288/330+/+ mice with a VRP delivering MERS-CoV spike protein protects mice from challenge with MERS-CoV.

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Acknowledgements

These studies were supported by grants from the National Institute of Allergy and Infectious Disease of the US NIH by awards HHSN272201000019I-HHSN27200003 (R.S.B. and M.T.H.), AI106772, AI108197, AI110700 and AI109761 (R.S.B.), and U19 AI100625 (R.S.B. and M.T.H.). GOF research considerations involving MERS-0 in vivo passage in mice and the current manuscript were both reviewed and approved by the funding agency, the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Generation of CRISPR–Cas9-modified mice was performed at the UNC Animal Models Core Facility under the direction of Dale Cowley.

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Author notes

  1. Mark T. Heise and Ralph S. Baric: These authors jointly supervised this work.

Authors and Affiliations

  1. Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, 27599, USA

    Adam S. Cockrell, Boyd L. Yount, Trevor Scobey, Kara Jensen, Madeline Douglas, Anne Beall & Ralph S. Baric

  2. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, 02215, USA

    Xian-Chun Tang & Wayne A. Marasco

  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Xian-Chun Tang & Wayne A. Marasco

  4. Departments of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, 27599, USA

    Mark T. Heise & Ralph S. Baric

  5. Departments of Genetics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, 27599, USA

    Mark T. Heise

Authors
  1. Adam S. Cockrell
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Contributions

A.S.C. conceived/designed, coordinated and executed the experiments, analysed the data and wrote the manuscript. B.L.Y. developed and recovered infectious clone viruses. T.S. completed mouse experiments. K.J. designed and completed immunological experiments. M.D. helped establish and maintain the mouse colony and perform molecular analyses. A.B. helped complete the mouse experiments. X.-C.T. and W.A.M. provided critical monoclonal antibody reagents. M.T.H. and R.S.B. conceived/designed the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Adam S. Cockrell, Mark T. Heise or Ralph S. Baric.

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Competing interests

W.A.M. has a financial interest in AbViro. The other authors declare no competing financial interests.

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Supplementary Table 1, Supplementary Figures 1–14 (PDF 2378 kb)

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Cockrell, A., Yount, B., Scobey, T. et al. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat Microbiol 2, 16226 (2017). https://doi.org/10.1038/nmicrobiol.2016.226

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