Author: Yinda, Claude Kwe; Port, Julia R.; Bushmaker, Trenton; Offei Owusu, Irene; Purushotham, Jyothi N.; Avanzato, Victoria A.; Fischer, Robert J.; Schulz, Jonathan E.; Holbrook, Myndi G.; Hebner, Madison J.; Rosenke, Rebecca; Thomas, Tina; Marzi, Andrea; Best, Sonja M.; de Wit, Emmie; Shaia, Carl; van Doremalen, Neeltje; Munster, Vincent J.
Title: K18-hACE2 mice develop respiratory disease resembling severe COVID-19 Cord-id: aa0tp5vb Document date: 2021_1_19
ID: aa0tp5vb
Snippet: 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
Document: 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 10(4) TCID(50) or 10(5) TCID(50), the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 10(5) TCID(50) 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 10(2) TCID(50) 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.
Search related documents:
Co phrase search for related documents- absence presence and acute ards respiratory distress syndrome: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11
- absence presence and acute respiratory syndrome: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- absence presence and adaptive immune response: 1, 2
- absence presence and additional study: 1, 2, 3, 4
- abundant sars antigen and acute respiratory syndrome: 1
- active virus and acute ards respiratory distress syndrome: 1, 2, 3
- active virus and acute respiratory syndrome: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
- active virus and adaptive immune cell: 1
- active virus and adaptive immune cell innate: 1
- active virus and adaptive immune response: 1, 2
- active virus replication and acute respiratory syndrome: 1, 2, 3, 4, 5, 6, 7
- active virus replication and adaptive immune response: 1
- acute ards respiratory distress syndrome and adaptive immune cell: 1, 2
- acute ards respiratory distress syndrome and adaptive immune cell innate: 1, 2
- acute ards respiratory distress syndrome and adaptive immune response: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11
- acute ards respiratory distress syndrome and additional study: 1, 2, 3, 4, 5
- acute respiratory syndrome and adaptive immune cell: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11
- acute respiratory syndrome and adaptive immune cell innate: 1, 2, 3, 4, 5, 6, 7
- acute respiratory syndrome and adaptive immune response: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
Co phrase search for related documents, hyperlinks ordered by date