Influenza virus A/Anhui/1/2013 (H7N9) replicates efficiently in the upper and lower respiratory tracts of cynomolgus macaques.
Influenza virus A/Anhui/1/2013 (H7N9) replicates efficiently in the upper and lower respiratory tracts of cynomolgus macaques.
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DOI：
10.1128/mbio.01331-14
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发表时间：
2014-08-12
期刊：
影响因子：
6.4
通讯作者：
Feldmann H
中科院分区：
文献类型：
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作者：
de Wit E;Rasmussen AL;Feldmann F;Bushmaker T;Martellaro C;Haddock E;Okumura A;Proll SC;Chang J;Gardner D;Katze MG;Munster VJ;Feldmann H
2013年3月，中国报告了三例人感染甲型流感病毒（H7N9）死亡病例。从那时起，人类病例不断积累。鉴于该病毒对公共卫生的重要性，我们在食蟹猴模型中对 H7N9 病毒进行了致病性研究，重点关注疾病的临床方面、上呼吸道和下呼吸道的放射学、组织学和基因表达谱的变化，以及感染期间全身细胞因子和趋化因子谱的变化。食蟹猴出现短暂的、轻度到重度的疾病，并有肺部浸润的放射学证据。病毒在上呼吸道和下呼吸道中复制，并在上呼吸道中持续复制，直到接种后 6 天实验结束。病毒主要通过喉咙传播。肺部的组织病理学变化与在人类中观察到的相似，尽管不太严重，具有弥漫性肺泡损伤、多形核细胞浸润、透明膜形成、肺细胞增生和纤维增殖性变化。对肺部病变基因表达谱的分析确定了 H7N9 感染期间参与组织损伤的途径，并为开发针对宿主反应而不是病毒复制的治疗方法提供了线索。总体而言，食蟹猴中的 H7N9 感染并不像人类中那么严重，这支持了针对人类 H7N9 感染所讨论的潜在医疗并发症在疾病严重程度中可能发挥的作用（H.N.Gao 等人，N.Engl.J.Med. 368:2277–2285, 2013, doi:10.1056/NEJMoa1305584）。甲型H7N9流感病毒于2013年初出现，此后人类病例不断出现。尽管 H7N9 病毒引起的人类疾病通常非常严重甚至致命，但大多数报告的 H7N9 病例发生在老年人和有基础疾病的人中。为了更好地了解这种病毒的致病性，健康的食蟹猴接种了甲型流感病毒H7N9。使用食蟹猴作为模型是因为最近发现，与其他常用动物模型相比，猕猴体内 H7N9 病毒的受体分布与人类更为相似。通过与之前的研究比较，我们得出结论，新出现的H7N9流感病毒对食蟹猴的致病性比季节性甲型流感病毒和大流行性H1N1病毒的大多数分离株更高，但比1918年西班牙流感病毒或高致病性禽流感（HPAI）H5N1病毒的致病性要低。
In March 2013, three fatal human cases of infection with influenza A virus (H7N9) were reported in China. Since then, human cases have been accumulating. Given the public health importance of this virus, we performed a pathogenicity study of the H7N9 virus in the cynomolgus macaque model, focusing on clinical aspects of disease, radiographic, histological, and gene expression profile changes in the upper and lower respiratory tracts, and changes in systemic cytokine and chemokine profiles during infection. Cynomolgus macaques developed transient, mild to severe disease with radiographic evidence of pulmonary infiltration. Virus replicated in the upper as well as lower respiratory tract, with sustained replication in the upper respiratory tract until the end of the experiment at 6 days after inoculation. Virus shedding occurred mainly via the throat. Histopathological changes in the lungs were similar to those observed in humans, albeit less severe, with diffuse alveolar damage, infiltration of polymorphonuclear cells, formation of hyaline membranes, pneumocyte hyperplasia, and fibroproliferative changes. Analysis of gene expression profiles in lung lesions identified pathways involved in tissue damage during H7N9 infection as well as leads for development of therapeutics targeting host responses rather than virus replication. Overall, H7N9 infection was not as severe in cynomolgus macaques as in humans, supporting the possible role of underlying medical complications in disease severity as discussed for human H7N9 infection (H. N. Gao et al., N. Engl. J. Med. 368:2277–2285, 2013, doi:10.1056/NEJMoa1305584). Influenza A virus H7N9 emerged early in 2013, and human cases have continued to emerge since then. Although H7N9 virus-induced disease in humans is often very severe and even lethal, the majority of reported H7N9 cases occurred in older people and people with underlying medical conditions. To better understand the pathogenicity of this virus, healthy cynomolgus macaques were inoculated with influenza A virus H7N9. Cynomolgus macaques were used as a model because the receptor distribution for H7N9 virus in macaques was recently shown to be more similar to that in humans than that of other frequently used animal models. From comparison with previous studies, we conclude that the emerging H7N9 influenza virus was more pathogenic in cynomolgus macaques than seasonal influenza A viruses and most isolates of the pandemic H1N1 virus but less pathogenic than the 1918 Spanish influenza virus or highly pathogenic avian influenza (HPAI) H5N1 virus.