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Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.

Authors :
Anthony C Marriott
Mike Dennis
Jennifer A Kane
Karen E Gooch
Graham Hatch
Sally Sharpe
Claudia Prevosto
Gail Leeming
Elsa-Gayle Zekeng
Karl J Staples
Graham Hall
Kathryn A Ryan
Simon Bate
Nathifa Moyo
Catherine J Whittaker
Bassam Hallis
Nigel J Silman
Ajit Lalvani
Tom M Wilkinson
Julian A Hiscox
James P Stewart
Miles W Carroll
Source :
PLoS ONE, Vol 11, Iss 6, p e0157887 (2016)
Publication Year :
2016
Publisher :
Public Library of Science (PLoS), 2016.

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.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
11
Issue :
6
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.0f136ad41145778e5c088d27afe3a2
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0157887