Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque
Integrated Clinical, Pathologic, Virologic, and Transcriptomic Analysis of H5N1 Influenza Virus-Induced Viral Pneumonia in the Rhesus Macaque
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DOI：
10.1128/jvi.00365-12
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发表时间：
2012-06-01
影响因子：
5.4
通讯作者：
Kawaoka, Yoshihiro
中科院分区：
文献类型：
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作者：
Shinya, Kyoko;Gao, Yuwei;Kawaoka, Yoshihiro
在流感病毒大流行的早期阶段和许多人类高致病性禽流感 (HPAI) H5N1 病毒感染病例中，经常报道病毒性肺炎。为了更好地了解这种疾病的发病机制，我们利用HPAI H5N1病毒在恒河猴中产生了非致死性病毒性肺炎（A/Anhui/2/2005；简称Anhui/2）。对受感染的猕猴进行了 14 天的监测，并在 6 个时间点收集组织样本进行病毒学、组织病理学和转录组学分析。感染后 12 小时至 3 天，Anhui/2 在肺部有效复制，并引起短暂但严重的肺炎，并在第 14 天开始消退。在 6 小时首次观察到肺部转录变化，血管通透性调节剂和中性粒细胞趋化剂表达增加与原位血清渗漏和中性粒细胞浸润增加相关。从 12 小时起，额外的炎症、抗病毒和凋亡基因上调，同时病毒抗原检测和免疫细胞群增加。第 6 天后，获得性免疫上调的转变很明显。已建立的免疫细胞分子标记的表达水平显示与病理结果显着相似，表明早期和强烈的中性粒细胞浸润，巨噬细胞积累略有延迟，以及丰富的晚期 T 淋巴细胞群体。我们还描述了调节独特的肺炎相关双相发热模式的假定机制。因此，这项研究首次使用全面、综合的方法来描述调节非人类灵长类动物中流感病毒引起的肺炎的特定分子机制，这是更好地管理人类流感病毒疾病的重要第一步。
Viral pneumonia has been frequently reported during early stages of influenza virus pandemics and in many human cases of highly pathogenic avian influenza (HPAI) H5N1 virus infection. To better understand the pathogenesis of this disease, we produced nonlethal viral pneumonia in rhesus macaques by using an HPAI H5N1 virus (A/Anhui/2/2005; referred to as Anhui/2). Infected macaques were monitored for 14 days, and tissue samples were collected at 6 time points for virologic, histopathologic, and transcriptomic analyses. Anhui/2 efficiently replicated in the lung from 12 h to 3 days postinfection (p.i.) and caused temporal but severe pneumonia that began to resolve by day 14. Lung transcriptional changes were first observed at 6 h, and increased expression of vascular permeability regulators and neutrophil chemoattractants correlated with increased serum leakage and neutrophil infiltration in situ. Additional inflammatory, antiviral, and apoptotic genes were upregulated from 12 h, concurrent with viral antigen detection and increasing immune cell populations. A shift toward upregulation of acquired immunity was apparent after day 6. Expression levels of established immune cell molecular markers revealed remarkable similarity with pathological findings, indicating early and robust neutrophil infiltration, a slight delay in macrophage accumulation, and abundant late populations of T lymphocytes. We also characterized the putative mechanisms regulating a unique, pneumonia-associated biphasic fever pattern. Thus, this study is the first to use a comprehensive and integrative approach to delineate specific molecular mechanisms regulating influenza virus-induced pneumonia in nonhuman primates, an important first step toward better management of human influenza virus disease.