Middle East Respiratory Syndrome Coronavirus Causes Multiple Organ Damage and Lethal Disease in Mice Transgenic for Human Dipeptidyl Peptidase 4
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Middle East respiratory syndrome coronavirus (MERS-CoV) causes life-threatening disease. Dipeptidyl peptidase 4 (DPP4) is the receptor for cell binding and entry. There is a need for small-animal models of MERS, but mice are not susceptible to MERS because murine dpp4 does not serve as a receptor. We developed transgenic mice expressing human DPP4 (hDPP4) under the control of the surfactant protein C promoter or cytokeratin 18 promoter that are susceptible to infection with MERS-CoV. Notably, mice expressing hDPP4 with the cytokeratin 18 promoter developed progressive, uniformly fatal disease following intranasal inoculation. High virus titers were present in lung and brain tissues 2 and 6 days after infection, respectively. MERS-CoV-infected lungs revealed mononuclear cell infiltration, alveolar edema, and microvascular thrombosis, with airways generally unaffected. Brain disease was observed, with the greatest involvement noted in the thalamus and brain stem. Animals immunized with a vaccine candidate were uniformly protected from lethal infection. These new mouse models of MERS-CoV should be useful for investigation of early disease mechanisms and therapeutic interventions.
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SARS-CoV, MERS-CoV, and HCoV-OCR43 were able to invade the murine CNS using the transcribrial route, infecting olfactory sensory neurons of the nasal cavity and passing to other neural cells, indicating that SARS-CoV-2 could use the same mechanism.
“In fact, SARS-CoV, MERS-CoV, and HCoV-OCR43 were able to invade the murine CNS using the transcribrial route, infecting olfactory sensory neurons of nasal cavity, and passing to other neural cells, indicating that SARS-CoV-2 could use the same mechanism [24, 35–37].”
From Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology (2021) · cites this paper as [37]
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- Authors
- Li, K., Wohlford-Lenane, C., Perlman, S., Zhao, J., Jewell, A. K., Reznikov, L. R., Gibson-Corley, K. N., Meyerholz, D. K., & McCray, P. B.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Li, Kun
- ORCID
- Venue
- Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-10-20
- Volume
- 213
- Issue
- 5
- Pages
- 712-722
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- PMC
- PMC4747621
- OpenAlex
- W2240913867
- Cited by
- 459
- References
- 47
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 20 · 2023: 27 · 2022: 59 · 2021: 116 · 2020: 183 · 2019: 12 · 2018: 4 · 2017: 7 · 2016: 10 · 2015: 1
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health
- NIH (PO1 AI060699, P30 DK-54759)
- Cell Morphology Core and Pathology Core
- Center for Gene Therapy for Cystic Fibrosis
- Cystic Fibrosis Foundation
- College of Medicine
- Roy J. Carver Charitable Trust
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Health Sciences › Medicine › Infectious Diseases › Viral Infections and Outbreaks Research
- Keywords
- MERS-CoV, dipeptidyl peptidase IV, viral receptor, surfactant protein C promoter, multiple organ injury, brain infection, lung pathology, vaccine immunization, mouse susceptibility
- MeSH terms
- Animals, Humans, Mice, Transgenic, RNA, Viral, Gene Expression Regulation, Enzymologic, Coronavirus Infections, Dipeptidyl Peptidase 4, Central Nervous System Viral Diseases, Mice, Middle East Respiratory Syndrome Coronavirus
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