K18-hACE2 mice develop respiratory disease resembling severe COVID-19.
SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-1...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1009195 |
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| author | Claude Kwe Yinda Julia R Port Trenton Bushmaker Irene Offei Owusu Jyothi N Purushotham Victoria A Avanzato Robert J Fischer Jonathan E Schulz Myndi G Holbrook Myndi G Holbrook Madison J Hebner Rebecca Rosenke Tina Thomas Andrea Marzi Sonja M Best Emmie de Wit Carl Shaia Neeltje van Doremalen Vincent J Munster |
| author_facet | Claude Kwe Yinda Julia R Port Trenton Bushmaker Irene Offei Owusu Jyothi N Purushotham Victoria A Avanzato Robert J Fischer Jonathan E Schulz Myndi G Holbrook Myndi G Holbrook Madison J Hebner Rebecca Rosenke Tina Thomas Andrea Marzi Sonja M Best Emmie de Wit Carl Shaia Neeltje van Doremalen Vincent J Munster |
| author_sort | Claude Kwe Yinda |
| collection | DOAJ |
| description | SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Additionally, we demonstrate that a mild disease course can be simulated by low dose infection with 102 TCID50 SARS-CoV-2, resulting in minimal clinical manifestation and near uniform survival. Taken together, these data support future application of this model to studies of pathogenesis and medical countermeasure development. |
| format | Article |
| id | doaj-art-798ae271b60d4475a045eac12954dcfe |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-798ae271b60d4475a045eac12954dcfe2025-08-20T02:23:18ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-01-01171e100919510.1371/journal.ppat.1009195K18-hACE2 mice develop respiratory disease resembling severe COVID-19.Claude Kwe YindaJulia R PortTrenton BushmakerIrene Offei OwusuJyothi N PurushothamVictoria A AvanzatoRobert J FischerJonathan E SchulzMyndi G HolbrookMyndi G HolbrookMadison J HebnerRebecca RosenkeTina ThomasAndrea MarziSonja M BestEmmie de WitCarl ShaiaNeeltje van DoremalenVincent J MunsterSARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Additionally, we demonstrate that a mild disease course can be simulated by low dose infection with 102 TCID50 SARS-CoV-2, resulting in minimal clinical manifestation and near uniform survival. Taken together, these data support future application of this model to studies of pathogenesis and medical countermeasure development.https://doi.org/10.1371/journal.ppat.1009195 |
| spellingShingle | Claude Kwe Yinda Julia R Port Trenton Bushmaker Irene Offei Owusu Jyothi N Purushotham Victoria A Avanzato Robert J Fischer Jonathan E Schulz Myndi G Holbrook Myndi G Holbrook Madison J Hebner Rebecca Rosenke Tina Thomas Andrea Marzi Sonja M Best Emmie de Wit Carl Shaia Neeltje van Doremalen Vincent J Munster K18-hACE2 mice develop respiratory disease resembling severe COVID-19. PLoS Pathogens |
| title | K18-hACE2 mice develop respiratory disease resembling severe COVID-19. |
| title_full | K18-hACE2 mice develop respiratory disease resembling severe COVID-19. |
| title_fullStr | K18-hACE2 mice develop respiratory disease resembling severe COVID-19. |
| title_full_unstemmed | K18-hACE2 mice develop respiratory disease resembling severe COVID-19. |
| title_short | K18-hACE2 mice develop respiratory disease resembling severe COVID-19. |
| title_sort | k18 hace2 mice develop respiratory disease resembling severe covid 19 |
| url | https://doi.org/10.1371/journal.ppat.1009195 |
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