Baskin Carole R, García-Sastre Adolfo, Tumpey Terrence M, Bielefeldt-Ohmann Helle, Carter Victoria S, Nistal-Villán Estanislao, Katze Michael G
Department of Comparative Medicine, University of Washington School of Medicine, Box 358070, Seattle, WA 98195, USA.
J Virol. 2004 Oct;78(19):10420-32. doi: 10.1128/JVI.78.19.10420-10432.2004.
For most severe viral pandemics such as influenza and AIDS, the exact contribution of individual viral genes to pathogenicity is still largely unknown. A necessary step toward that understanding is a systematic comparison of different influenza virus strains at the level of transcriptional regulation in the host as a whole and interpretation of these complex genetic changes in the context of multifactorial clinical outcomes and pathology. We conducted a study by infecting pigtailed macaques (Macaca nemestrina) with a genetically reconstructed strain of human influenza H1N1 A/Texas/36/91 virus and hypothesized not only that these animals would respond to the virus similarly to humans, but that gene expression patterns in the lungs and tracheobronchial lymph nodes would fit into a coherent and complete picture of the host-virus interactions during infection. The disease observed in infected macaques simulated uncomplicated influenza in humans. Clinical signs and an antibody response appeared with induction of interferon and B-cell activation pathways, respectively. Transcriptional activation of inflammatory cells and apoptotic pathways coincided with gross and histopathological signs of inflammation, with tissue damage and concurrent signs of repair. Additionally, cDNA microarrays offered new evidence of the importance of cytotoxic T cells and natural killer cells throughout infection. With this experiment, we confirmed the suitability of the nonhuman primate model in the quest for understanding the individual and joint contributions of viral genes to influenza virus pathogenesis by using cDNA microarray technology and a reverse genetics approach.
对于大多数严重的病毒性大流行，如流感和艾滋病，单个病毒基因对致病性的确切贡献在很大程度上仍不清楚。朝着理解这一点迈出的必要一步是在宿主整体转录调控水平上对不同流感病毒株进行系统比较，并在多因素临床结果和病理学背景下解释这些复杂的基因变化。我们通过用基因重组的人类甲型H1N1流感病毒A/德州/36/91株感染猪尾猕猴（食蟹猴）开展了一项研究，并假设这些动物对该病毒的反应不仅与人类相似，而且肺和气管支气管淋巴结中的基因表达模式将符合感染期间宿主-病毒相互作用的连贯且完整的图景。在受感染猕猴中观察到的疾病模拟了人类的轻症流感。临床症状和抗体反应分别随着干扰素诱导和B细胞激活途径而出现。炎症细胞的转录激活和凋亡途径与炎症的大体和组织病理学特征、组织损伤以及同时出现的修复迹象相一致。此外，cDNA微阵列提供了关于细胞毒性T细胞和自然杀伤细胞在整个感染过程中重要性的新证据。通过这个实验，我们利用cDNA微阵列技术和反向遗传学方法，证实了非人类灵长类动物模型在探索病毒基因对流感病毒发病机制的个体和共同贡献方面的适用性。
