Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.
Influenza A Virus Challenge Models in Cynomolgus Macaques Using the Authentic Inhaled Aerosol and Intra-Nasal Routes of Infection.
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DOI：
10.1371/journal.pone.0157887
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Carroll MW
中科院分区：
文献类型：
--
作者：
Marriott AC;Dennis M;Kane JA;Gooch KE;Hatch G;Sharpe S;Prevosto C;Leeming G;Zekeng EG;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
在系统发育相关性、生理学和免疫系统方面，非人灵长类动物是最接近人类的动物，可用于甲型流感病毒攻毒研究。先前的研究表明，食蟹猴（Macaca fascicularis）允许感染H1N1pdm流感病毒。这些研究通常使用联合攻击途径，其中大多数是气管内递送和高剂量病毒（> 107感染单位）。本文描述了食蟹猴中新型攻毒途径（吸入气雾剂、鼻内滴注）和低至中等剂量（103至106空斑形成单位）H1N1pdm病毒的结果。在所有四个攻毒组中均检测到病毒复制和血清转化的证据，尽管该疾病为亚临床疾病。鼻内激发导致局限于鼻腔的感染。低剂量（103空斑形成单位）未导致可检测的感染性病毒脱落，但1000倍高剂量导致所有鼻内激发动物的病毒脱落。相比之下，气雾剂和气管内激发途径导致整个呼吸道感染，尽管与高剂量鼻内激发组相比，动物之间鼻腔散毒的重现性较低。气管内和气溶胶激发诱导了短暂的淋巴细胞减少，与流感感染的人中观察到的相似，并且与鼻内激发组相比，在这些组中观察到血液中更大的病毒特异性细胞免疫应答。在攻击后第5至7天检测到肺巨噬细胞和先天免疫应答基因的活化。病毒学和免疫学的感染动力学与人甲型流感病毒感染大致一致。这些更真实的感染模型将在确定新实体针对不太严重（因此更常见）的流感感染的抗流感功效方面是有价值的。
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.