To date, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reportedly infected over 630 million people, leading to the deaths of more than 6.5 million people. Despite expansive investigation of its pathogenesis and the development of vaccines and therapeutics, research in preclinical models must continue to ensure that we can combat the continuing COVID-19 and future pandemics. Two exemplary animal models – Syrian golden hamsters and K18-promoter-driven human ACE2-expressing (K18-hACE2) mice – recapitulate the human pathology, immune response and clinical manifestations of COVID-19, and are also accessible with low cost. However, there are vast differences in the severity of disease in these models, with mild clinical manifestations in the hamsters and high lethality in the mice.
Jeong and colleagues intranasally infected Syrian golden hamsters and K18-hACE2 mice with the same dose of SARS-CoV-2, resulting in mild clinical signs in hamsters, such as minor decreases in body weight, and severe manifestations in mice, leading to death by 7 days post-infection (dpi). The authors thoroughly interrogated the infection in these animals to elucidate the mechanisms behind the differing clinical outcomes. They used in situ hybridization imaging to show that SARS-CoV-2 infection was mainly confined to microvillar club (∼88%) and ciliated (∼12%) cell subsets in the bronchus region of hamsters. These infected cells were rapidly eliminated, with high levels of cell death apparent at 2 dpi. By 5 dpi, in the hamsters, the infected area was highly infiltrated with B and CD8+ T cells, which are important for clearing infected cells. Surprisingly, lung pathology was more severe in hamsters than in mice at 5 and 7 dpi, with imaging revealing markers of bronchioalveolar adenoma and bronchopneumonia in hamsters. However, after 7 dpi, pulmonary lesions and adaptive immune cell accumulation were ameliorated, with only regenerative hyperplasia apparent in the bronchus at 14 dpi. Overall, the initial robust immune response was key in limiting and resolving SARS-CoV-2 infection in hamsters.
By contrast, SARS-CoV-2 primarily infected the alveolar area of mouse lungs, with type 1 alveolar cells comprising roughly 97% of total infected cells, and very few infected cells were eliminated. The infection also spread to distal organs, such as the spleen at 2 dpi and the brain at 7 dpi, which resulted in inflammatory cell death and histopathological damage in several organs. B and T cells progressively accumulated in the mouse lungs up until death at 7 dpi, but the extent of infiltration was much lower than that in hamsters at early time points. The deficient clearance of infected cells in the mice was potentially due to the lower levels of CD8+ T cells, which are associated with COVID-19 mortality in humans. Taken together, these results indicate that the pathology of SARS-CoV-2 infection in K18-hACE2 mice mimics severe COVID-19 in humans.
COVID-19 pathology is highly variable in humans, and the mechanism behind this variability needs to be thoroughly explored to optimise prognosis and treatment. Direct comparison of these two integral disease models not only informs future research using animal models of COVID-19, but also provides comprehensive insights into variation in COVID-19 pathology.
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