1. Influenza A virus challenge models in Cynomolgus macaques using the authentic inhaled aerosol and intra-nasal routes of infection
- Author
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Marriott, AC, Dennis, M, Kane, JA, Gooch, KE, Hatch, G, Sharpe, S, Prevosto, C, Leeming, G, Zekeng, E-G, Staples, KJ, Hall, G, Ryan, KA, Bate, S, Moyo, N, Whittaker, CJ, Hallis, B, Silman, NJ, Lalvani, A, Wilkinson, TM, Hiscox, JA, Stewart, JP, Carroll, MW, Pöhlmann, S, Medical Research Council (MRC), and Pöhlmann, S more...
- Subjects
Male ,Pulmonology ,Monkeys ,Severity of Illness Index ,Madin Darby Canine Kidney Cells ,Animal Cells ,Protein Interaction Mapping ,Lymphocytes ,lcsh:Science ,Immune Response ,Plaque-forming unit ,Mammals ,3. Good health ,Physical Sciences ,Science & Technology - Other Topics ,Cellular Types ,Viral load ,Bronchoalveolar Lavage Fluid ,Macaque ,Primates ,Materials by Structure ,Immune Cells ,030106 microbiology ,Materials Science ,Immunology ,RESPIRATORY-TRACT ,Microbiology ,03 medical and health sciences ,Interferon-gamma ,biology.animal ,Macrophages, Alveolar ,Humans ,CELL ,Medicine and health sciences ,Science & Technology ,Blood Cells ,Macrophages ,lcsh:R ,Organisms ,Computational Biology ,Virology ,Influenza ,RNA extraction ,Macaca fascicularis ,030104 developmental biology ,Mixtures ,lcsh:Q ,PATHOGENICITY ,RESPONSES ,0301 basic medicine ,RNA viruses ,Viral Diseases ,Proteome ,lcsh:Medicine ,VACCINE ,medicine.disease_cause ,Virus Replication ,White Blood Cells ,Influenza A Virus, H1N1 Subtype ,Influenza A virus ,PROTECTION ,Pathology and laboratory medicine ,Multidisciplinary ,NONHUMAN-PRIMATES ,Medical microbiology ,Viral Load ,respiratory system ,Virus Shedding ,Multidisciplinary Sciences ,Infectious Diseases ,Vertebrates ,Viruses ,Pathogens ,Research Article ,TRANSMISSION ,General Science & Technology ,Biology ,Virus ,Immune system ,Extraction techniques ,Dogs ,Orthomyxoviridae Infections ,Lymphopenia ,MD Multidisciplinary ,Old World monkeys ,Administration, Inhalation ,medicine ,Animals ,Influenza viruses ,Viral shedding ,Administration, Intranasal ,Aerosols ,Biology and life sciences ,Viral pathogens ,Cell Biology ,Influenza A virus subtype H5N1 ,Microbial pathogens ,Research and analysis methods ,Disease Models, Animal ,Amniotes ,Respiratory Infections ,AVIAN INFLUENZA ,Orthomyxoviruses - 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. more...
- Published
- 2016