Abstract
While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals. To further understand differing COVID-19 manifestations in patients of different ages, three age groups of ferrets are infected with SARS-CoV-2. Although SARS-CoV-2 is isolated from all ferrets regardless of age, aged ferrets (≥3 years old) show higher viral loads, longer nasal virus shedding, and more severe lung inflammatory cell infiltration, and clinical symptoms compared to juvenile (≤6 months) and young adult (1–2 years) groups. Furthermore, direct contact ferrets co-housed with the virus-infected aged group shed more virus than direct-contact ferrets co-housed with virus-infected juvenile or young adult ferrets. Transcriptome analysis of aged ferret lungs reveals strong enrichment of gene sets related to type I interferon, activated T cells, and M1 macrophage responses, mimicking the gene expression profile of severe COVID-19 patients. Thus, SARS-CoV-2-infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARS-CoV-2.
Highlights
While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals
While ferrets less than six months of age (G1) showed no increase in temperature, both 1–2 year-old (G2) and more than three-year-old (G3) groups of SARS-CoV-2 infected ferrets showed elevated temperatures at 2–6 dpi, where the G3 group showed a prolonged elevated temperature even at 10 dpi (Fig. 2a). This trend was associated with changes in body weight, where the G1 group showed less than 5% weight loss during the entire SARS-CoV-2 infection period, while the G2 and G3 groups showed a maximal 10% weight loss at 6 dpi, followed by a rapid recovery of the G2 group from 6 dpi but not the G3 group (Fig. 2b)
To compare clinical manifestations of SARS-CoV-2 infection, we developed a clinical assessment scoring system to evaluate clinical symptom (CS) values based on a 20-min observation period of cough, rhinorrhea, and reduced activity
Summary
While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals. SARS-CoV-2infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARSCoV-2. While human clinical studies are highly valuable, a number of limitations including ethical issues, behavioral and environmental variables, and medical history of the patients, may impede identification of the fundamental cause of the disease in a timely manner. This necessitates the development of an appropriate animal model to aid in understanding transmission and pathogenesis of SARS-CoV-2, as well as elucidating host immune responses against SARS-CoV-2 infection. The current hACE2 transgenic mouse model, which expresses human ACE2, the entry receptor for SARS-CoV-2, showed weight loss and virus replication in the lung following SARS-CoV-2 infection
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