Young-Il Kim^1,2,3,7, Kwang-Min Yu^1,2,7, June-Young Koh^4,7, Eun-Ha Kim^1,2, Se-Mi Kim^1,2,3, Eun Ji Kim^1,2, Mark Anthony B. Casel^1,2, Rare Rollon¹, Seung-Gyu Jang¹, Min-Suk Song^1,2, Su-Jin Park⁵, Hye Won Jeong¹, Eung-Gook Kim¹, Ok-Jun Lee¹, Yong-Dae Kim¹, Younho Choi⁶, Shin-Ae Lee⁶, Youn Jung Choi⁶, Su-Hyung Park⁴, Jae U. Jung^6,* & Young Ki Choi^1,2,3,*

¹College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Republic of Korea. ²Zoonotic Infectious Diseases Research Center, Chungbuk National University, Cheongju, Korea. ³Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon 34126, Republic of Korea. ⁴Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. ⁵Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea. ⁶Cancer Biology Department and Global Center for Pathogens Research and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. ⁷These authors contributed equally: Young-Il Kim, Kwang-Min Yu, June-Young Koh.

^*Corresponding author.

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.