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

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) shows 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.

ORGANISM(S): Mustela putorius furo

PROVIDER: GSE189619 | GEO | 2021/12/31

REPOSITORIES: GEO

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Project description:Background: Type I interferons (IFNs) are essential to the clearance of viral diseases, in part by initiating upregulation of IFN regulated genes (IRGs). A clear distinction between genes upregulated directly by virus and genes upregulated by secondary IFN production has not been made. Here we investigated the genes regulated by IFN-a2b compared to the genes regulated by SARS-CoV infection in ferrets. Methods: We characterized early host immune responses in peripheral blood and lung necropsies of ferrets injected with IFN-a2b or infected with SARS-CoV/Tor 2 strain, using microarray analysis on the Affymetrix platform. Results: We identified a common IRG signature that was upregulated in both SARS-CoV infected ferrets as well as in ferrets injected with IFN-a2b. We also identified unique patterns of gene expression for leukocyte activation, cell adhesion and complement pathways between IFN-a2b injection and SARS-CoV infection. Conclusions: Our results define the effects of IFN-a2b on the immune system of ferrets highlighting genes regulated by IFN during SARS-CoV infection. We have shown the similarities and differences of top funcional gene groups as well as pathways that play key roles in early immune responses in ferrets in response to IFN-a2b or SARS-CoV. Key words: ferret, gene expression, SARS, interferon. Keywords: time course In experiments with IFN-a2b, for peripheral blood, 15 ferrets were randomly allocated to 3 groups: Day 0, 5 ferrets (no IFN injection), day 1, 6 ferrets (injected), and day 2, 4 ferrets (injected). For lung necropsies of injected ferrets with IFN-a2b, we used 12 ferrets in 3 groups: 4 ferrets, day 0 (no IFN injection), 4 ferrets, day 1 (injected) and 4 ferrets, day 2 (injected). Experimental groups for SARS-CoV infection was as follows: For peripheral blood, 3 and 4 ferrets for day 0 (no infection) and day 2 (infection) respectively. For lung neceropsies, a total of 9 ferrets in 3 groups, each with 3 replicates for day 0 (no infection), day 1 (infection) and day 2 (infection).

Project description:Objectives: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the worldwide COVID-19 pandemic. While SARS-CoV-2 can infect people of all ages and both sexes, senior populations are at greatest risk of severe disease and worse outcomes, and sexual dimorphism has been reported in COVID-19. COVID-19 causes damage to multiple organ systems, including the brain. Neurological symptoms are widely observed in patients with Covid-19, with many survivors suffering from persistent neurological impairment, potentially accelerating Alzheimer’s disease (AD). This study aims to investigate the mechanisms underlying the impact of age, and sex on neuroinflammation due to SARS-CoV-2 infection using mouse models. Methods: Wild-type C57BL/6 mice were subjected to intranasal inoculation of SARS-CoV-2 lineage B.1.351, followed by daily body weight monitoring. At 7 dpi, viral burden and inflammatory cytokine/chemokine responses in the lung and brain were determined by quantitative RT-PCR, followed by immunohistochemical and transcriptomic analyses. Results: Older age, male sex, showed increased lung viral loads and severity of SARS-CoV-2 infection in mice. No viral RNA was detected in the brains of infected mice; however, IL-6 and CCL2 mRNA increased significantly, particularly in brains of old and APOE4 mice. Unbiased brain RNA-seq/transcriptomic analysis showed that SARS-CoV-2 infection caused significant changes in gene expression profiles, and pathway analysis identified innate immunity and defense response to virus and other organisms as the major molecular networks affected in the brain by SARS-CoV-2 infection. Conclusions: Our findings demonstrate that age, and sex, modify the progression and outcome of SARS-CoV-2 infection. SARS-CoV-2 infection triggers neuroinflammatory responses despite the lack of detectable virus in the brain. Changes in molecular networks of innate immunity and defense response to microorganisms underlie the impact of SARS-CoV-2 infection in the brain. These findings in mice mimic epidemiological and clinical observations in humans with Covid-19.

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

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