Age-dependent pathogenic characteristics of SARS-CoV-2 infection in ferrets

Abstract

The sero-prevalence of SARS-CoV-2 in healthy people is not significantly different among age groups, but persons age 65 years or older had strikingly higher COVID-19 mortality compared to younger individuals. To understand COVID-19 manifestations in patients of different ages, ferrets in three age groups were infected with SARS-CoV-2. Although SARS-CoV-2 was isolated from all ferrets regardless of age, aged ferrets (≥3 years old) showed higher viral load, longer nasal virus shedding, and more severe lung inflammatory cell infiltration and clinical symptom compared to ≤6 months juvenile and 1-2 years young adult groups. Transcriptome analysis of aged ferret lungs revealed strong enrichment of gene sets related to type I interferon, activated T cell, 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 an age-associated infection, transmission, and pathogenesis of SARS-CoV-2.

Age-related susceptibility of ferrets to SARS-CoV-2 infection

“…Our findings showing higher susceptibility of aged ferrets to SARS-CoV-2 infection in the present study mirror clinical observations in humans, which point to increased susceptibility and higher levels of virus replication in the respiratory tract of older people when compared to young children 12,14 . Additionally, results presented here corroborate findings of a recent study by Kim and collaborators 35 , who showed age-related differences in viral load in the respiratory tract, and lung histopathology in ferrets inoculated with SARS-CoV-2. This study also showed that expression levels of genes related to the interferon (IFN) pathway, activated T cells, and macrophage responses were increased in older ferrets following SARS-CoV-2 infection 35 .…”

“…Additionally, results presented here corroborate findings of a recent study by Kim and collaborators 35 , who showed age-related differences in viral load in the respiratory tract, and lung histopathology in ferrets inoculated with SARS-CoV-2. This study also showed that expression levels of genes related to the interferon (IFN) pathway, activated T cells, and macrophage responses were increased in older ferrets following SARS-CoV-2 infection 35 . These changes are likely due to enhanced immune responses following higher viral replication in aged animals.…”

Animal models of SARS-CoV-2 transmission

“…Since ferrets develop no or relatively mild disease and histopathological changes, combined with RT-PCR detectable viral loads and shedding from the respiratory tract, ferrets are regarded an optimal model for asymptomatic or mild disease in humans and are often used in transmission studies [ 92 ]. Recently, it was shown that aged ferret (>3 years old) have higher viral loads, longer shedding and more severe lung inflammatory cell infiltration, accompanied by more clinical symptoms (fever and weight loss) compared to juvenile and young adult ferrets [ 93 ].…”

Animal models for SARS‐CoV‐2 infection and pathology

“…158,159 Intranasal inoculation of SARS-CoV-2 induces the clinical symptoms that observed in COVID-19 patients, including reduced activity, nasal discharge, sneezing, wheezing, occasional cough, and increased body temperature in infected ferrets. 160,161 The clinical symptoms are manifested on 2 dpi and recover to the initial state on 12 dpi. The body weight loss is controversial in several studies on SARS-CoV-2-infected ferrets.…”