Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease
| Autor: | Joshua D. Shamblin, Eric M. Mucker, Brian D. Carey, Aura R. Garrison, Hypaitia B. Rauch, Jay W. Hooper, Xiankun Zeng, Jeffrey M. Smith, Bradley S. Hollidge, April M. Babka, Collin Fitzpatrick, Rebecca L. Brocato, Curtis R. Cline, Catherine V. Badger, Jun Liu, Lauren E. White, Joseph W. Golden |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Genetically modified mouse Pneumonia Viral Mice Transgenic Disease Peptidyl-Dipeptidase A Lung injury Mouse models Severe Acute Respiratory Syndrome Virus Replication Severity of Illness Index Keratin 18 Proinflammatory cytokine Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Cause of Death medicine Animals Humans Lung Pandemics Molecular pathology Infectious disease business.industry Respiratory disease COVID-19 General Medicine respiratory system medicine.disease respiratory tract diseases Survival Rate Disease Models Animal 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology Angiotensin-converting enzyme 2 Disease Progression Medicine Female Angiotensin-Converting Enzyme 2 Coronavirus Infections business Research Article |
| Zdroj: | JCI Insight, Vol 5, Iss 19 (2020) JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | The emergence of SARS-CoV-2 has created an international health crisis, and small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection owing to low-affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here, we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promoter (K18). In contrast to nontransgenic mice, intranasal exposure of K18-hACE2 animals to 2 different doses of SARS-CoV-2 resulted in acute disease, including weight loss, lung injury, brain infection, and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals showed increases in transcripts involved in lung injury and inflammatory cytokines. In the low-dose challenge groups, there was a survival advantage in the female mice, with 60% surviving infection, whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared with female mice. To our knowledge, this is the first highly lethal murine infection model for SARS-CoV-2 and should be valuable for the study of SARS-CoV-2 pathogenesis and for the assessment of MCMs. A highly lethal murine infection model for SARS-CoV-2 using mice transgenic for the human ACE2 protein is described. |
| Databáze: | OpenAIRE |
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