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.
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Anthony C
AC
Marriott
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Mike
M
Dennis
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Jennifer A
JA
Kane
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Karen E
KE
Gooch
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Graham
G
Hatch
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Sally
S
Sharpe
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Claudia
C
Prevosto
Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
Gail
G
Leeming
Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
Elsa-Gayle
EG
Zekeng
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Karl J
KJ
Staples
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Graham
G
Hall
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Kathryn A
KA
Ryan
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Simon
S
Bate
Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
Nathifa
N
Moyo
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Catherine J
CJ
Whittaker
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Bassam
B
Hallis
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Nigel J
NJ
Silman
Department of Respiratory Infections, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Ajit
A
Lalvani
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Tom M
TM
Wilkinson
Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
Julian A
JA
Hiscox
Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
James P
JP
Stewart
National Infection Service, Public Health England, Porton Down, Wiltshire, United Kingdom.
Miles W
MW
Carroll
D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000336:Aerosols / Q000008:administration & dosage; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019295:Computational Biology; D004195:Disease Models, Animal; D004285:Dogs; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000821:virology*; D008231:Lymphopenia / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008252:Macaca fascicularis / Q000276:immunology* / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000821:virology*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009976:Orthomyxoviridae Infections / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000821:virology*; D025941:Protein Interaction Mapping; D020543:Proteome / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D019562:Viral Load / Q000276:immunology; D014779:Virus Replication / Q000502:physiology; D017201:Virus Shedding / Q000502:physiology
D000336:Aerosols; D020543:Proteome; D007371:Interferon-gamma