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

Kim, Young Il; Yu, Kwang-Min; Koh, June-Young; Kim, Eunha; Kim, Se‐Mi; Kim, Young Ho; Casel, Mark Anthony B.; Rollon, Rare; Jang, Seung-Gyu; Song, Min‐Suk; Park, Su‐Jin; Jeong, Hye Won; Kim, Eung‐Gook; Lee, Ok-Jun; Choi, Younho; Lee, Shin-Ae; Park, Su–Hyung; Jung, Jae U.; Choi, Young Ki

doi:10.21203/rs.3.rs-131380/v2

Cited by 10 publications

(15 citation statements)

References 49 publications

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“…Our findings showing higher susceptibility of aged ferrets to SARS-CoV-2 infection in the present study parallel clinical observations in humans, which point to increased susceptibility and higher levels of virus replication in the respiratory tract of older people compared to young children ( 8 , 10 ). Additionally, results presented here corroborate findings of a recent study by Kim and collaborators ( 31 ), 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 ( 31 ).…”

Section: Discussionsupporting

confidence: 92%

“…Additionally, results presented here corroborate findings of a recent study by Kim and collaborators ( 31 ), 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 ( 31 ). These changes are likely due to enhanced immune responses following higher viral replication in aged animals.…”

Section: Discussionsupporting

confidence: 92%

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Age-Related Susceptibility of Ferrets to SARS-CoV-2 Infection

Martins

Fernandes

Joshi

et al. 2022

J Virol

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Susceptibility to SARS-CoV-2 and the outcome of COVID-19 have been linked to underlying health conditions and the age of affected individuals. Here we assessed the effect of age on SARS-CoV-2 infection using a ferret model. For this, young (6-month-old) and aged (18-to-39-month-old) ferrets were inoculated intranasally with various doses of SARS-CoV-2. By using infectious virus shedding in respiratory secretions and seroconversion, we estimated that the infectious dose of SARS-CoV-2 in aged animals is ∼32 plaque forming units (PFU) per animal while in young animals it was estimated to be ∼100 PFU. We showed that viral replication in the upper respiratory tract and shedding in respiratory secretions is enhanced in aged ferrets when compared to young animals. Similar to observations in humans, this was associated with higher transcription levels of two key viral entry factors - ACE2 and TMPRSS2 - in the upper respiratory tract of aged ferrets. Importance In humans, ACE2 and TMPRSS2 are expressed in various cells and tissues, and a differential expression have been described in young and old people, with a higher level of expressing cells being detected in the nasal brushing of older people when compared to young individuals. We described the same pattern occurring in ferrets and we demonstrated that age affects susceptibility of ferrets to SARS-CoV-2. Aged animals were more likely to get infected when exposed to lower infectious dose of the virus when compared to young animals and the viral replication in the URT and shedding is enhanced in aged ferrets. Together these results suggest that the higher infectivity and enhanced ability of SARS-CoV-2 to replicate in aged individuals is associated – at least in part – with transcription levels of ACE2 and TMPRSS2 at the sites of virus entry. The young and aged ferret model developed here may represent a great platform to assess age-related differences in SARS-CoV-2 infection dynamics and replication.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Age-Related Susceptibility of Ferrets to SARS-CoV-2 Infection

Martins

Fernandes

Joshi

et al. 2022

J Virol

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“…Three-year-old ferrets had fevers that lasted out past 10 dpi. In addition, older ferrets lost more weight upon infection and regained it more slowly than younger ferrets [ 80 ]. More severe lung pathology also was noted in the older ferrets at 5 dpi.…”

Section: Age and Comorbiditiesmentioning

confidence: 99%

Advances and gaps in SARS-CoV-2 infection models

et al. 2022

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The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to recapitulate COVID-19 demographic variables such as comorbidities and age.

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“…Nonhuman primate (12)(13)(14), ferret (15)(16)(17) and mouse (18) models that have been developed to understand SARS-CoV-2 pathogenesis and test vaccine and therapeutics efficacies display a mild course of disease. The lack of overt symptoms in NHPs and ethical constraints due to the sheer numbers required to recapitulate low frequency human cases with severe clinical manifestations limits the ability to understand all aspects of the disease and vaccine effectiveness.…”

Section: Introductionmentioning

confidence: 99%

Attenuated activation of pulmonary immune cells in mRNA-1273–vaccinated hamsters after SARS-CoV-2 infection

Meyer¹,

Wang²,

Edwards³

et al. 2021

Journal of Clinical Investigation

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The mRNA-1273 vaccine was determined to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interim Phase 3 results and subsequently received an emergency use authorization by the FDA. Human studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit severe SARS-CoV-2 disease similar to hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and non-human primates, low level virus replication in mRNA-1273 vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high resolution analysis which is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mockvaccinated hamsters. Our results support the use of mRNA-1273 in a two-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.

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

Cited by 10 publications

References 49 publications

Age-Related Susceptibility of Ferrets to SARS-CoV-2 Infection

Age-Related Susceptibility of Ferrets to SARS-CoV-2 Infection

Advances and gaps in SARS-CoV-2 infection models

Attenuated activation of pulmonary immune cells in mRNA-1273–vaccinated hamsters after SARS-CoV-2 infection

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