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

Anthony C. Marriott, Michael 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 Silman, Ajit Lalvani, Tom M. Wilkinson, Julian A. HiscoxJames P. Stewart, Miles Carroll

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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 subclinical. 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.

Original languageEnglish
Article numbere0157887
JournalPLoS ONE
Volume11
Issue number6
DOIs
Publication statusPublished - 1 Jun 2016

Bibliographical note

Publisher Copyright:
© 2016 Marriott et al. 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 credited.

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