Bertram Stephanie, Thiele Swantje, Dreier Carola, Resa-Infante Patricia, Preuß Annette, van Riel Debby, Mok Chris K P, Schwalm Folker, Peiris Joseph S M, Klenk Hans-Dieter, Gabriel Gülsah
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany; Center for Structural and Cellular Biology in Medicine, University of Lübeck, Lübeck, Germany.
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
Am J Pathol. 2017 Apr;187(4):831-840. doi: 10.1016/j.ajpath.2016.12.017. Epub 2017 Feb 9.
The acute respiratory distress syndrome (ARDS) is the leading cause of death in influenza A virus (IAV)-infected patients. Hereby, the cellular importin-α7 gene plays a major role. It promotes viral replication in the lung, thereby increasing the risk for the development of pneumonia complicated by ARDS. Herein, we analyzed whether the recently emerged H7N9 avian IAV has already adapted to human importin-α7 use, which is associated with high-level virus replication in the mammalian lung. Using a cell-based viral polymerase activity assay, we could detect a decreased H7N9 IAV polymerase activity when importin-α7 was silenced by siRNA. Moreover, virus replication was diminished in the murine cells lacking the importin-α7 gene. Consistently, importin-α7 knockout mice presented reduced pulmonary virus titers and lung lesions as well as enhanced survival rates compared to wild-type mice. In summary, our results show that H7N9 IAV have acquired distinct features of adaptation to human host factors that enable enhanced virulence in mammals. In particular, adaptation to human importin-α7 mediates elevated virus replication in the mammalian lung, which might have contributed to ARDS observed in H7N9-infected patients.
急性呼吸窘迫综合征（ARDS）是甲型流感病毒（IAV）感染患者死亡的主要原因。在此，细胞输入蛋白α7基因起主要作用。它促进病毒在肺部的复制，从而增加并发ARDS的肺炎发生风险。在此，我们分析了最近出现的H7N9禽流感病毒是否已经适应利用人类输入蛋白α7，这与病毒在哺乳动物肺部的高水平复制有关。使用基于细胞的病毒聚合酶活性测定法，当通过小干扰RNA（siRNA）使输入蛋白α7沉默时，我们能够检测到H7N9 IAV聚合酶活性降低。此外，在缺乏输入蛋白α7基因的小鼠细胞中病毒复制减少。一致地，与野生型小鼠相比，输入蛋白α7基因敲除小鼠的肺部病毒滴度和肺损伤降低，存活率提高。总之，我们的结果表明，H7N9 IAV已经获得了适应人类宿主因子的独特特征，从而在哺乳动物中增强了毒力。特别是，对人类输入蛋白α7的适应介导了病毒在哺乳动物肺部的复制增加，这可能是导致H7N9感染患者出现ARDS的原因。
