Lethal Infection of K18- hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus

McCray, Paul B.; Pewe, Lecia; Wohlford-Lenane, Christine; Hickey, Melissa; Manzel, Lori; Shi, Lei; Netland, Jason; Jia, Hong Peng; Halabi, Carmen; Sigmund, Curt D.; Meyerholz, David K.; Kirby, Patricia; Look, Dwight C.; Perlman, Stanley

doi:10.1128/jvi.02012-06

Cited by 1,010SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections StudiesCOVID-19 Clinical Research Studies

Lethal Infection of K18- hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus

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McCray, Paul B., Pewe, Lecia, Wohlford-Lenane, Christine, Hickey, Melissa, Manzel, Lori, Shi, Lei, Netland, Jason, Jia, Hong Peng +6 more·2007·Journal of Virology

DOI 10.1128/jvi.02012-06PMC PMC1797474

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Abstract

The severe acute respiratory syndrome (SARS), caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. While SARS-CoV infection has not recurred to a significant extent since 2003, it still remains a potential threat. Understanding of SARS and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. This model of lethal infection with SARS-CoV should be useful for studies of pathogenesis and for the development of antiviral therapies.

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Intranasal SARS-CoV-1 inoculation in K18-hACE2 mutant mice resulted in viral presence throughout the CNS, associated with local inflammatory mediators, respiratory dysfunction, and high mortality, with only mild lung infection.
“Intranasal SARS-CoV-1 inoculation (80% homology to SARS-CoV-2) in K18-hACE2 mutant mice (with the human form of ACE-2) resulted in the viral presence throughout the CNS, and was associated with local inflammatory mediators, respiratory dysfunction, and high mortality, with only mild lung infection [171, 172].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [171]
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 [35]

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Authors: McCray, P. B., Pewe, L., Wohlford-Lenane, C., Hickey, M., Manzel, L., Shi, L., Netland, J., Jia, H. P., Halabi, C., Sigmund, C. D., Meyerholz, D. K., Kirby, P., Look, D. C., & Perlman, S.
Affiliations: University of Iowa (US)
Microbiology
Departments of Pediatrics
Internal Medicine
Interdisciplinary Programs in Immunology
Pathology
Corresponding author: McCray, Paul B.
Perlman, Stanley
ORCID: McCray, Paul B.
Pewe, Lecia
Shi, Lei
Netland, Jason
Jia, Hong Peng
Halabi, Carmen
Sigmund, Curt D.
Meyerholz, David K.
Kirby, Patricia
Perlman, Stanley
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 2007-01-15
Volume: 81
Issue: 2
Pages: 813-821
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.02012-06
PMC: PMC1797474
OpenAlex: W2043343078
Cited by: 1,010
References: 43
Citations by year: 2026: 34 · 2025: 48 · 2024: 111 · 2023: 124 · 2022: 188 · 2021: 221 · 2020: 208 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 3
FWCI: 6.40
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Cystic Fibrosis Foundation
National Institutes of Health (P30 DK, PO1AI060699, AI060699)
National Institute of General Medical Sciences (T32GM007337)
National Institute of Allergy and Infectious Diseases (P01AI060699)
National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK 54759, P30DK054759)
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 › COVID-19 Clinical Research Studies
Keywords: SARS-CoV, SARS, hACE2 transgenic mice, airway epithelium, brain infection, macrophage infiltration, lymphocyte infiltration, inflammatory cytokines, chemokines, pathogenesis, antiviral therapy
MeSH terms: Animals, Brain, Disease Models, Animal, Epithelial Cells, Humans, Peptidyl-Dipeptidase A, Lung, Mice, Inbred C57BL, Mice, Transgenic, Severe Acute Respiratory Syndrome, Severe acute respiratory syndrome-related coronavirus, Mice, Keratin-18

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Lethal Infection of K18- hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus

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