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.
Highlights
Influenza A virus (IAV) is an RNA virus of the orthomyxovirus family
To establish an authentic model for human challenge by IAV, we chose to infect cynomolgus macaques (Macaca fascicularis) with A/California/04/09 (H1N1) (A/Cal/04/09). This virus has been extensively characterised in the ferret model by us and others [22], in which animals it usually produces a mild disease course representative of a typical non-complicated human H1N1pdm infection
None of the challenge routes used resulted in overt clinical disease in the non-human primate (NHP), which was unsurprising given the reported lack of clinical signs observed in other studies using much higher challenge doses (>7x106 pfu) of A/Cal/04/09 [8, 23]
Summary
IAV strains are endemic and largely asymptomatic in wild birds but certain strains can cause severe disease outbreaks in domestic poultry that are of economic importance. IAV strains circulate in pigs, causing swine influenza. Seasonal influenza in humans is caused by IAV (and influenza B virus) strains that circulate in the global population and is managed by annual vaccination of those at high risk of serious disease (e.g. the elderly, those with chronic respiratory or cardiac disease, and pregnant women). The wildlife reservoir, antigenic evolution and rapid development of resistance to antiviral drugs mean there is a constant need to research and develop novel interventions. This relies on the availability of authentic animal models
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