Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the paediatric, elderly and immune-compromised populations^1,2. A gap in our understanding of hRSV disease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists^3-6; however, the role of these proteins in viral pathogenesis is incompletely understood. Here, we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralogue of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 wild type or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I interferon responses, suppression of dendritic cell maturation and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV-associated morbidity and mortality.

中文翻译：

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人类呼吸道合胞病毒NS​​1介导的宿主反应调节的结构基础。

人类呼吸道合胞病毒（hRSV）是儿童，老年人和免疫功能低下的人群^1,2的发病率和死亡率的主要原因。在我们对hRSV疾病病理学的理解中，一个空白是病毒编码的免疫拮抗剂与限制hRSV复制的宿主成分之间的相互作用。hRSV编码非结构性（NS）蛋白，它们是重要的免疫拮​​抗剂^3-6; 但是，这些蛋白质在病毒发病机理中的作用尚不完全清楚。在这里，我们报告hRSV NS1蛋白的晶体结构，这表明NS1是hRSV基质（M）蛋白的结构旁系。与M共享结构折叠的比较分析揭示了NS1独特的区域。对单独或重组RSV中的NS1野生型或突变体的研究表明，NS1独特的结构区域有助于调节宿主反应，包括抑制I型干扰素反应，抑制树突状细胞成熟和促进炎症反应。感染重组RSV的A549细胞的转录特征在多个宿主途径中显示出显着差异，这表明NS1在调节宿主反应中的作用可能比以前意识到的要大。