National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
J Virol. 2018 Dec 10;93(1). doi: 10.1128/JVI.01655-18. Print 2019 Jan 1.
Human noroviruses (huNoVs), which cause epidemic acute gastroenteritis, recognize histo-blood group antigens (HBGAs) as host attachment factors affecting host susceptibility. HuNoVs are genetically diverse, containing at least 31 genotypes in the two major genogroups (genogroup I [GI] and GII). Three GII genotypes, GII genotype 17 (GII.17), GII.13, and GII.21, form a unique genetic lineage, in which the GII.17 genotype retains the conventional GII HBGA binding site (HBS), while the GII.13/21 genotypes acquire a completely new HBS. To understand the molecular bases behind these evolutionary changes, we solved the crystal structures of the HBGA binding protruding domains of (i) an early GII.17 variant (the 1978 variant) that does not bind or binds weakly to HBGAs, (ii) the new GII.17 variant (the 2014/15 variant) that binds A/B/H antigens strongly via an optimized GII HBS, and (iii) a GII.13 variant (the 2010 variant) that binds the Lewis a (Le) antigen via the new HBS. These serial, high-resolution structural data enable a comprehensive structural comparison to understand the evolutionary changes of the GII.17/13/21 lineage, including the emergence of the new HBS of the GII.13/21 sublineage and the possible HBS optimization of the recent GII.17 variant for an enhanced HBGA binding ability. Our study elucidates the structural adaptations of the GII.17/13/21 lineage through distinct evolutionary paths, which may allow a theory explaining huNoV adaptations and evolutions to be put forward. Our understanding of the molecular bases behind the interplays between human noroviruses and their host glycan ligands, as well as their evolutionary changes over time with alterations in their host ligand binding capability and host susceptibility, remains limited. By solving the crystal structures of the glycan ligand binding protruding (P) domains with or without glycan ligands of three representative noroviruses of the GII.17/13/21 genetic lineage, we elucidated the molecular bases of the human norovirus-glycan interactions of this special genetic lineage. We present solid evidence on how noroviruses of this genetic lineage evolved via different evolutionary paths to (i) optimize their glycan binding site for higher glycan binding function and (ii) acquire a completely new glycan binding site for new ligands. Our data shed light on the mechanism of the structural adaptations of human noroviruses through different evolutionary paths, facilitating our understanding of human norovirus adaptations, evolutions, and epidemiology.
人类诺如病毒（HuNoVs）是引起流行性急性肠胃炎的病原体，其识别组织血型抗原（HBGA）作为影响宿主易感性的宿主附着因子。HuNoVs 具有遗传多样性，在两个主要基因群（基因群 I [GI]和 GII）中至少包含 31 种基因型。三种 GII 基因型，GII 基因型 17（GII.17）、GII.13 和 GII.21，形成一个独特的遗传谱系，其中 GII.17 基因型保留了传统的 GII HBGA 结合位点（HBS），而 GII.13/21 基因型获得了一个全新的 HBS。为了了解这些进化变化背后的分子基础，我们解析了（i）早期 GII.17 变体（1978 变体）的 HBGA 结合突出结构域、（ii）新的 GII.17 变体（2014/15 变体）的 HBGA 结合突出结构域以及（iii）GII.13 变体（2010 变体）的 HBGA 结合突出结构域的晶体结构，这三种变体分别是不结合或弱结合 HBGAs 的变体、通过优化的 GII HBS 强烈结合 A/B/H 抗原的变体以及通过新的 HBS 结合 Lewis a（Le）抗原的变体。这些连续的、高分辨率的结构数据使我们能够进行全面的结构比较，以了解 GII.17/13/21 谱系的进化变化，包括 GII.13/21 亚谱系中新 HBS 的出现以及最近 GII.17 变体可能发生的 HBS 优化，以增强 HBGA 结合能力。我们的研究通过不同的进化途径阐明了 GII.17/13/21 谱系的结构适应性，这可能为解释人类诺如病毒的适应和进化提供理论依据。我们对人类诺如病毒与其宿主聚糖配体之间相互作用以及它们随着宿主配体结合能力和宿主易感性的变化而随时间发生进化的分子基础的理解仍然有限。通过解析三种代表 GII.17/13/21 遗传谱系的诺如病毒与聚糖配体结合突出（P）域结合或不结合聚糖配体的晶体结构，我们阐明了该特殊遗传谱系中人类诺如病毒与聚糖相互作用的分子基础。我们提供了确凿的证据，证明了该遗传谱系中的诺如病毒如何通过不同的进化途径（i）优化其聚糖结合位点以提高聚糖结合功能，以及（ii）获得全新的聚糖结合位点以结合新的配体。我们的数据揭示了人类诺如病毒通过不同进化途径进行结构适应性的机制，有助于我们理解人类诺如病毒的适应、进化和流行病学。
