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Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir

Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza vi...

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Autores principales: Marriott, Anthony C., Dove, Brian K., Whittaker, Catherine J., Bruce, Christine, Ryan, Kathryn A., Bean, Thomas J., Rayner, Emma, Pearson, Geoff, Taylor, Irene, Dowall, Stuart, Plank, Jenna, Newman, Edmund, Barclay, Wendy S., Dimmock, Nigel J., Easton, Andrew J., Hallis, Bassam, Silman, Nigel J., Carroll, Miles W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978028/
https://www.ncbi.nlm.nih.gov/pubmed/24709834
http://dx.doi.org/10.1371/journal.pone.0094090
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author Marriott, Anthony C.
Dove, Brian K.
Whittaker, Catherine J.
Bruce, Christine
Ryan, Kathryn A.
Bean, Thomas J.
Rayner, Emma
Pearson, Geoff
Taylor, Irene
Dowall, Stuart
Plank, Jenna
Newman, Edmund
Barclay, Wendy S.
Dimmock, Nigel J.
Easton, Andrew J.
Hallis, Bassam
Silman, Nigel J.
Carroll, Miles W.
author_facet Marriott, Anthony C.
Dove, Brian K.
Whittaker, Catherine J.
Bruce, Christine
Ryan, Kathryn A.
Bean, Thomas J.
Rayner, Emma
Pearson, Geoff
Taylor, Irene
Dowall, Stuart
Plank, Jenna
Newman, Edmund
Barclay, Wendy S.
Dimmock, Nigel J.
Easton, Andrew J.
Hallis, Bassam
Silman, Nigel J.
Carroll, Miles W.
author_sort Marriott, Anthony C.
collection PubMed
description Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza virus (H1N1pdm09) induces mild to moderate respiratory disease in infected ferrets, following inoculation with 10(6) plaque-forming units (pfu) of virus. We have demonstrated that reducing the challenge dose to 10(2) pfu delays the onset of clinical signs by 1 day, and results in a modest reduction in clinical signs, and a less rapid nasal cavity innate immune response. There was also a delay in virus production in the upper respiratory tract, this was up to 9-fold greater and virus shedding was prolonged. Progression of infection to the lower respiratory tract was not noticeably delayed by the reduction in virus challenge. A dose of 10(4) pfu gave an infection that was intermediate between those of the 10(6) pfu and 10(2) pfu doses. To address the hypothesis that using a more authentic low challenge dose would facilitate a more sensitive model for antiviral efficacy, we used the well-known neuraminidase inhibitor, oseltamivir. Oseltamivir-treated and untreated ferrets were challenged with high (10(6) pfu) and low (10(2) pfu) doses of influenza H1N1pdm09 virus. The low dose treated ferrets showed significant delays in innate immune response and virus shedding, delayed onset of pathological changes in the nasal cavity, and reduced pathological changes and viral RNA load in the lung, relative to untreated ferrets. Importantly, these observations were not seen in treated animals when the high dose challenge was used. In summary, low dose challenge gives a disease that more closely parallels the disease parameters of human influenza infection, and provides an improved pre-clinical model for the assessment of influenza therapeutics, and potentially, influenza vaccines.
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spelling pubmed-39780282014-04-11 Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir Marriott, Anthony C. Dove, Brian K. Whittaker, Catherine J. Bruce, Christine Ryan, Kathryn A. Bean, Thomas J. Rayner, Emma Pearson, Geoff Taylor, Irene Dowall, Stuart Plank, Jenna Newman, Edmund Barclay, Wendy S. Dimmock, Nigel J. Easton, Andrew J. Hallis, Bassam Silman, Nigel J. Carroll, Miles W. PLoS One Research Article Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza virus (H1N1pdm09) induces mild to moderate respiratory disease in infected ferrets, following inoculation with 10(6) plaque-forming units (pfu) of virus. We have demonstrated that reducing the challenge dose to 10(2) pfu delays the onset of clinical signs by 1 day, and results in a modest reduction in clinical signs, and a less rapid nasal cavity innate immune response. There was also a delay in virus production in the upper respiratory tract, this was up to 9-fold greater and virus shedding was prolonged. Progression of infection to the lower respiratory tract was not noticeably delayed by the reduction in virus challenge. A dose of 10(4) pfu gave an infection that was intermediate between those of the 10(6) pfu and 10(2) pfu doses. To address the hypothesis that using a more authentic low challenge dose would facilitate a more sensitive model for antiviral efficacy, we used the well-known neuraminidase inhibitor, oseltamivir. Oseltamivir-treated and untreated ferrets were challenged with high (10(6) pfu) and low (10(2) pfu) doses of influenza H1N1pdm09 virus. The low dose treated ferrets showed significant delays in innate immune response and virus shedding, delayed onset of pathological changes in the nasal cavity, and reduced pathological changes and viral RNA load in the lung, relative to untreated ferrets. Importantly, these observations were not seen in treated animals when the high dose challenge was used. In summary, low dose challenge gives a disease that more closely parallels the disease parameters of human influenza infection, and provides an improved pre-clinical model for the assessment of influenza therapeutics, and potentially, influenza vaccines. Public Library of Science 2014-04-07 /pmc/articles/PMC3978028/ /pubmed/24709834 http://dx.doi.org/10.1371/journal.pone.0094090 Text en © 2014 Marriott et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Marriott, Anthony C.
Dove, Brian K.
Whittaker, Catherine J.
Bruce, Christine
Ryan, Kathryn A.
Bean, Thomas J.
Rayner, Emma
Pearson, Geoff
Taylor, Irene
Dowall, Stuart
Plank, Jenna
Newman, Edmund
Barclay, Wendy S.
Dimmock, Nigel J.
Easton, Andrew J.
Hallis, Bassam
Silman, Nigel J.
Carroll, Miles W.
Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir
title Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir
title_full Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir
title_fullStr Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir
title_full_unstemmed Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir
title_short Low Dose Influenza Virus Challenge in the Ferret Leads to Increased Virus Shedding and Greater Sensitivity to Oseltamivir
title_sort low dose influenza virus challenge in the ferret leads to increased virus shedding and greater sensitivity to oseltamivir
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978028/
https://www.ncbi.nlm.nih.gov/pubmed/24709834
http://dx.doi.org/10.1371/journal.pone.0094090
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