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Influenza A virus challenge models in cynomolgus macaques using the authentic inhaled aerosol and intra-nasal routes of infection

Influenza A virus challenge models in cynomolgus macaques using the authentic inhaled aerosol and intra-nasal routes of infection
Influenza A virus challenge models in cynomolgus macaques using the authentic inhaled aerosol and intra-nasal routes of infection
Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.
1932-6203
1-21
Marriott, Anthony C.
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Dennis, Mike
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Kane, Jennifer A.
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Gooch, Karen E.
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Hatch, Graham
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Sharpe, Sally
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Prevosto, Claudia
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Leeming, Gail
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Zekeng, Elsa-Gayle
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Staples, Karl J.
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Hall, Graham
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Ryan, Kathryn A.
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Bate, Simon
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Moyo, Nathifa
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Whittaker, Catherine J.
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Hallis, Bassam
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Silman, Nigel J.
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Lalvani, Ajit
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Wilkinson, Tom W.
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Hiscox, Julian A.
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Stewart, James P.
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Carroll, Miles W.
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Marriott, Anthony C.
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Dennis, Mike
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Kane, Jennifer A.
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Gooch, Karen E.
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Hatch, Graham
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Sharpe, Sally
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Prevosto, Claudia
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Leeming, Gail
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Zekeng, Elsa-Gayle
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Staples, Karl J.
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Hall, Graham
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Ryan, Kathryn A.
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Bate, Simon
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Moyo, Nathifa
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Whittaker, Catherine J.
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Hallis, Bassam
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Silman, Nigel J.
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Lalvani, Ajit
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Wilkinson, Tom W.
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Hiscox, Julian A.
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Stewart, James P.
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Carroll, Miles W.
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Marriott, Anthony C., Dennis, Mike, Kane, Jennifer A., Gooch, Karen E., Hatch, Graham, Sharpe, Sally, Prevosto, Claudia, Leeming, Gail, Zekeng, Elsa-Gayle, Staples, Karl J., Hall, Graham, Ryan, Kathryn A., Bate, Simon, Moyo, Nathifa, Whittaker, Catherine J., Hallis, Bassam, Silman, Nigel J., Lalvani, Ajit, Wilkinson, Tom W., Hiscox, Julian A., Stewart, James P. and Carroll, Miles W. (2016) Influenza A virus challenge models in cynomolgus macaques using the authentic inhaled aerosol and intra-nasal routes of infection. PLoS ONE, 11 (6), 1-21. (doi:10.1371/journal.pone.0157887). (PMID:27311020)

Record type: Article

Abstract

Non-human primates are the animals closest to humans for use in influenza A virus challenge studies, in terms of their phylogenetic relatedness, physiology and immune systems. Previous studies have shown that cynomolgus macaques (Macaca fascicularis) are permissive for infection with H1N1pdm influenza virus. These studies have typically used combined challenge routes, with the majority being intra-tracheal delivery, and high doses of virus (> 107 infectious units). This paper describes the outcome of novel challenge routes (inhaled aerosol, intra-nasal instillation) and low to moderate doses (103 to 106 plaque forming units) of H1N1pdm virus in cynomolgus macaques. Evidence of virus replication and sero-conversion were detected in all four challenge groups, although the disease was sub-clinical. Intra-nasal challenge led to an infection confined to the nasal cavity. A low dose (103 plaque forming units) did not lead to detectable infectious virus shedding, but a 1000-fold higher dose led to virus shedding in all intra-nasal challenged animals. In contrast, aerosol and intra-tracheal challenge routes led to infections throughout the respiratory tract, although shedding from the nasal cavity was less reproducible between animals compared to the high-dose intra-nasal challenge group. Intra-tracheal and aerosol challenges induced a transient lymphopaenia, similar to that observed in influenza-infected humans, and greater virus-specific cellular immune responses in the blood were observed in these groups in comparison to the intra-nasal challenge groups. Activation of lung macrophages and innate immune response genes was detected at days 5 to 7 post-challenge. The kinetics of infection, both virological and immunological, were broadly in line with human influenza A virus infections. These more authentic infection models will be valuable in the determination of anti-influenza efficacy of novel entities against less severe (and thus more common) influenza infections.

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Accepted/In Press date: 6 June 2016
e-pub ahead of print date: 16 June 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 397003
URI: https://eprints.soton.ac.uk/id/eprint/397003
ISSN: 1932-6203
PURE UUID: 1b974e6b-5f01-4d5b-aa29-277d33d83f0f
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 20 Jun 2016 10:24
Last modified: 10 Dec 2019 01:43

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Contributors

Author: Anthony C. Marriott
Author: Mike Dennis
Author: Jennifer A. Kane
Author: Karen E. Gooch
Author: Graham Hatch
Author: Sally Sharpe
Author: Claudia Prevosto
Author: Gail Leeming
Author: Elsa-Gayle Zekeng
Author: Karl J. Staples ORCID iD
Author: Graham Hall
Author: Kathryn A. Ryan
Author: Simon Bate
Author: Nathifa Moyo
Author: Catherine J. Whittaker
Author: Bassam Hallis
Author: Nigel J. Silman
Author: Ajit Lalvani
Author: Julian A. Hiscox
Author: James P. Stewart
Author: Miles W. Carroll

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