K18-hACE2 mice develop respiratory disease resembling severe COVID-19

• Published in: PLoS pathogens Vol. 17; no. 1; p. e1009195
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.01.2021; Public Library of Science (PLoS)
• Subjects: Alveoli; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - immunology; Animals; Antigens; Biology and life sciences; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - immunology; COVID-19 - pathology; COVID-19 - virology; Cytokeratin; Disease Models, Animal; Dose-response relationship (Biochemistry); Edema; Engineering and Technology; Epithelial cells; Female; Fibrin; Gastrointestinal system; Gastrointestinal tract; Gene expression; Genomes; Health aspects; Humans; Hyperplasia; Immunoreactivity; Infections; Inflammation; Irradiated; Keratin-18 - genetics; Keratin-18 - immunology; Kidneys; Leukocytes (neutrophilic); Lung - immunology; Lung - pathology; Lungs; Lymphocytes; Lymphocytes - immunology; Macrophages; Macrophages - immunology; Male; Medicine and health sciences; Mice; Mice, Transgenic; Necrosis; Neutrophils; Organs; Pathology; Pneumocytes; Pneumonia; Promoter Regions, Genetic; Promoters (Genetics); Rectum; Research and Analysis Methods; Respiratory diseases; SARS-CoV-2 - physiology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Shedding; Trachea - immunology; Trachea - virology; Transgenic animals; Viral diseases; Viruses; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009195

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.