Intranasal infection of ferrets with SARS-CoV-2 as a model for asymptomatic human infection

Helen E. Everett; Fabian Z.X. Lean; Alexander M.P. Byrne; Pauline M. van Diemen; Shelley Rhodes; Joe James; Benjamin Mollett; Vivien J. Coward; Paul Skinner; Caroline J. Warren; Kevin R. Bewley; Samantha Watson; Shellene Hurley; Kathryn A. Ryan; Yper Hall; Hugh Simmons; Alejandro Núñez; Miles Carroll; Ian H. Brown; Sharon M. Brookes

doi:10.3390/v13010113

Intranasal infection of ferrets with SARS-CoV-2 as a model for asymptomatic human infection

Helen E. Everett, Fabian Z.X. Lean, Alexander M.P. Byrne, Pauline M. van Diemen, Shelley Rhodes, Joe James, Benjamin Mollett, Vivien J. Coward, Paul Skinner, Caroline J. Warren, Kevin R. Bewley, Samantha Watson, Shellene Hurley, Kathryn A. Ryan, Yper Hall, Hugh Simmons, Alejandro Núñez, Miles Carroll, Ian H. Brown, Sharon M. Brookes

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Abstract

Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.

Original language	English
Article number	113
Number of pages	14
Journal	Viruses
Volume	13
Issue number	1
DOIs	https://doi.org/10.3390/v13010113
Publication status	Published - 15 Jan 2021

Bibliographical note

Funding Information: This study was funded by the UK Department for Environment, Food & Rural Affairs (DEFRA) and the devolved Scottish and Welsh administrations, Grant numbers SE0557 and SV3700. The funder had no role in study design, analysis, interpretation or writing of this article. A virus isolate was obtained through the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 871029.

Open Access: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Citation: Everett, H.E.; Lean, F.Z.X.; Byrne, A.M.P.; van Diemen, P.M.; Rhodes, S.; James, J.; Mollett, B.; Coward, V.J.; Skinner, P.; Warren, C.J.; Bewley, K.R.; Watson, S.; Hurley, S.; Ryan, K.A.; Hall, Y.; Simmons, H.; Núñez, A.; Carroll, M.W.; Brown, I.H.; Brookes, S.M. Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection. Viruses 2021, 13, 113.

DOI: https://doi.org/10.3390/v13010113

Keywords

Ferret
Olfactory neuronal cells
SARS-CoV-2
Y453F

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Everett2021IntranasalInfectionOfFerretsWithSARS-CoV-2AsAModelForAsymptomaticHumanInfectionVirusesFinal published version, 1.86 MBLicence: CC BY

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Everett, H. E., Lean, F. Z. X., Byrne, A. M. P., van Diemen, P. M., Rhodes, S., James, J., Mollett, B., Coward, V. J., Skinner, P., Warren, C. J., Bewley, K. R., Watson, S., Hurley, S., Ryan, K. A., Hall, Y., Simmons, H., Núñez, A., Carroll, M., Brown, I. H., & Brookes, S. M. (2021). Intranasal infection of ferrets with SARS-CoV-2 as a model for asymptomatic human infection. Viruses, 13(1), Article 113. https://doi.org/10.3390/v13010113

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title = "Intranasal infection of ferrets with SARS-CoV-2 as a model for asymptomatic human infection",

abstract = "Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.",

keywords = "Ferret, Olfactory neuronal cells, SARS-CoV-2, Y453F",

author = "Everett, {Helen E.} and Lean, {Fabian Z.X.} and Byrne, {Alexander M.P.} and {van Diemen}, {Pauline M.} and Shelley Rhodes and Joe James and Benjamin Mollett and Coward, {Vivien J.} and Paul Skinner and Warren, {Caroline J.} and Bewley, {Kevin R.} and Samantha Watson and Shellene Hurley and Ryan, {Kathryn A.} and Yper Hall and Hugh Simmons and Alejandro N{\'u}{\~n}ez and Miles Carroll and Brown, {Ian H.} and Brookes, {Sharon M.}",

note = "Funding Information: This study was funded by the UK Department for Environment, Food & Rural Affairs (DEFRA) and the devolved Scottish and Welsh administrations, Grant numbers SE0557 and SV3700. The funder had no role in study design, analysis, interpretation or writing of this article. A virus isolate was obtained through the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under grant agreement No 871029. Open Access: This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland. Citation: Everett, H.E.; Lean, F.Z.X.; Byrne, A.M.P.; van Diemen, P.M.; Rhodes, S.; James, J.; Mollett, B.; Coward, V.J.; Skinner, P.; Warren, C.J.; Bewley, K.R.; Watson, S.; Hurley, S.; Ryan, K.A.; Hall, Y.; Simmons, H.; N{\'u}{\~n}ez, A.; Carroll, M.W.; Brown, I.H.; Brookes, S.M. Intranasal Infection of Ferrets with SARS-CoV-2 as a Model for Asymptomatic Human Infection. Viruses 2021, 13, 113. DOI: https://doi.org/10.3390/v13010113",

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Everett, HE, Lean, FZX, Byrne, AMP, van Diemen, PM, Rhodes, S, James, J, Mollett, B, Coward, VJ, Skinner, P, Warren, CJ, Bewley, KR, Watson, S, Hurley, S, Ryan, KA, Hall, Y, Simmons, H, Núñez, A, Carroll, M, Brown, IH & Brookes, SM 2021, 'Intranasal infection of ferrets with SARS-CoV-2 as a model for asymptomatic human infection', Viruses, vol. 13, no. 1, 113. https://doi.org/10.3390/v13010113

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AU - Everett, Helen E.

AU - Lean, Fabian Z.X.

AU - Byrne, Alexander M.P.

AU - van Diemen, Pauline M.

AU - Rhodes, Shelley

AU - James, Joe

AU - Mollett, Benjamin

AU - Coward, Vivien J.

AU - Skinner, Paul

AU - Warren, Caroline J.

AU - Bewley, Kevin R.

AU - Watson, Samantha

AU - Hurley, Shellene

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AU - Hall, Yper

AU - Simmons, Hugh

AU - Núñez, Alejandro

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PY - 2021/1/15

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N2 - Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.

AB - Ferrets were experimentally inoculated with SARS-CoV-2 (severe acute respiratory syndrome (SARS)-related coronavirus 2) to assess infection dynamics and host response. During the resulting subclinical infection, viral RNA was monitored between 2 and 21 days post-inoculation (dpi), and reached a peak in the upper respiratory cavity between 4 and 6 dpi. Viral genomic sequence analysis in samples from three animals identified the Y453F nucleotide substitution relative to the inoculum. Viral RNA was also detected in environmental samples, specifically in swabs of ferret fur. Microscopy analysis revealed viral protein and RNA in upper respiratory tract tissues, notably in cells of the respiratory and olfactory mucosae of the nasal turbinates, including olfactory neuronal cells. Antibody responses to the spike and nucleoprotein were detected from 21 dpi, but virus-neutralizing activity was low. A second intranasal inoculation (re-exposure) of two ferrets after a 17-day interval did not produce re-initiation of viral RNA shedding, but did amplify the humoral response in one animal. Therefore, ferrets can be experimentally infected with SARS-CoV-2 to model human asymptomatic infection.

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KW - Olfactory neuronal cells

KW - SARS-CoV-2

KW - Y453F

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SN - 1999-4915

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JF - Viruses

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ER -

Intranasal infection of ferrets with SARS-CoV-2 as a model for asymptomatic human infection

Abstract

Bibliographical note

Keywords

UN SDGs

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