Abstract：
Human adenoviruses (HAdVs) are small DNA viruses that generally cause mild disease. Certain strains, particularly those belonging to species B HAdVs, can cause severe pneumonia and have a relatively high mortality rate. Little is known about the molecular aspects of how these highly pathogenic species affect the infected cell and how they suppress innate immunity. The present study provides molecular insights into how species B adenoviruses suppress the interferon signaling pathway. Our study shows that these viruses, unlike HAdV-C2, are resistant to type I interferon. This resistance likely arises due to the highly efficient suppression of interferon-stimulated gene expression. Unlike in HAdV-C2, HAdV-B7 and B14 sequester STAT2 and RNA polymerase II from interferon-stimulated gene promoters in infected cells. This results in suppressed interferon- stimulated gene activation. In addition, we show that RuvBL1 and RuvBL2, cofactors important for RNA polymerase II recruitment to promoters and interferon-stimulated gene activation, are redirected to the cytoplasm forming high molecular weight complexes that, likely, are unable to associate with chromatin. Proteomic analysis also identified key differences in the way these viruses affect the host cell, providing insights into species B-associated high pathogenicity. Curiously, we observed that at the level of protein expression changes to the infected cell, HAdV-C2 and B7 were more similar than those of the same species, B7 and B14. Collectively, our study represents the first such study of innate immune suppression by the highly pathogenic HAdV-B7 and B14, laying an important foundation for future investigations.IMPORTANCEHuman adenoviruses form a large family of double-stranded DNA viruses known for a variety of usually mild diseases. Certain strains of human adenovirus cause severe pneumonia leading to much higher mortality and morbidity than most other strains. The reasons for this enhanced pathogenicity are unknown. Our study provides a molecular investigation of how these highly pathogenic strains might inactivate the interferon signaling pathway, highlighting the lack of sensitivity of these viruses to type I interferon in general while providing a global picture of how viral changes in cellular proteins drive worse disease outcomes.
摘要：
人腺病毒(HAdV)是通常引起轻度疾病的小DNA病毒。某些菌株，特别是那些属于BHAdV的物种，可引起严重的肺炎，死亡率相对较高。关于这些高致病性物种如何影响受感染细胞以及它们如何抑制先天免疫的分子方面知之甚少。本研究提供了有关物种B腺病毒如何抑制干扰素信号通路的分子见解。我们的研究表明，这些病毒，与HAdV-C2不同,对I型干扰素具有抗性。这种抗性可能是由于干扰素刺激的基因表达的高效抑制而产生的。与HAdV-C2不同，HAdV-B7和B14从感染细胞中干扰素刺激的基因启动子中隔离了STAT2和RNA聚合酶II。这导致抑制的干扰素刺激的基因激活。此外,我们显示RuvBL1和RuvBL2是RNA聚合酶II募集到启动子和干扰素刺激的基因激活的重要辅因子，被重定向到细胞质形成高分子量复合物，很可能,无法与染色质联系。蛋白质组学分析还确定了这些病毒影响宿主细胞的方式的关键差异，提供对物种B相关高致病性的见解。奇怪的是,我们观察到感染细胞的蛋白质表达水平发生变化，HAdV-C2和B7比同一物种更相似，B7和B14。总的来说，我们的研究代表了高致病性HAdV-B7和B14对先天免疫抑制的首次此类研究,为未来的研究奠定了重要的基础.重要人类腺病毒形成了双链DNA病毒的大家族，已知有多种通常轻微的疾病。某些人腺病毒菌株引起严重肺炎,导致比大多数其他菌株高得多的死亡率和发病率。这种致病性增强的原因是未知的。我们的研究提供了这些高致病性菌株如何使干扰素信号通路失活的分子研究。强调这些病毒对I型干扰素缺乏敏感性，同时提供了细胞蛋白中的病毒变化如何导致更糟糕的疾病结局的全球图景。
