Structural Analysis of a Rabbit Hemorrhagic Disease Virus Binding to Histo-Blood Group Antigens
Structural Analysis of a Rabbit Hemorrhagic Disease Virus Binding to Histo-Blood Group Antigens
复制标题
DOI：
10.1128/jvi.02832-14
复制
发表时间：
2015-02-01
影响因子：
5.4
通讯作者：
Hansman, Grant S.
中科院分区：
文献类型：
--
作者：
Leuthold, Mila M.;Dalton, Kevin P.;Hansman, Grant S.
兔出血性疾病病毒（RHDV）是杯状病毒科（兔病毒属）的成员。 RHDV 具有高度传染性，附着在消化道或呼吸道的上皮细胞上，导致大面积病变，死亡率很高。最近出现了 RHDV 的新变种（称为 RHDVb），之前接种疫苗的兔子似乎对这种新病毒株几乎没有保护作用。与人类诺如病毒（杯状病毒科，诺如病毒属）类似，RHDV 结合组织血型抗原 (HBGA)，这被认为对感染很重要。在这里，我们使用 X 射线晶体学报告了 RHDVb 衣壳突出结构域（P 结构域）上的 HBGA 结合位点。 HBGA 结合口袋位于 P 结构域侧面的带负电荷的贴片中和二聚体界面处。两个单体的残基都有助于 HBGA 结合，并涉及直接氢键和水介导的相互作用的网络。不同 RHDV 毒株的氨基酸序列比对表明，与 HBGA 的 ABH-岩藻糖直接相互作用的残基（Asp472、Asn474 和 Ser479）高度保守。这一结果表明不同的 RHDV 毒株也可以在相同的口袋处结合 HBGA。此外，RHDVb 和人类基因组 II 诺如病毒之间的一些 HBGA 结合特征相似，这表明 HBGA 结合相互作用可能存在趋同进化。需要对其他 RHDV 毒株进行进一步的结构研究，以便更好地了解不同 RHDV 毒株之间的 HBGA 结合机制。重要性我们首次使用 X 射线晶体学鉴定了 RHDVb P 结构域上的 HBGA 结合位点。我们的结果表明 RHDVb 和人类基因组 II 诺如病毒具有相似的 HBGA 结合相互作用。最近发现，合成的HBGA或表达HBGA的肠道细菌可以增强B细胞中人类基因组II诺如病毒的感染。考虑到 RHDVb 和基因组 II 诺如病毒与 HBGA 的相互作用类似，类似的细胞培养系统也可能适用于 RHDVb。总而言之，这些新发现将扩展我们对杯状病毒 HBGA 相互作用的理解，并可能有助于阐明 HBGA 在杯状病毒感染中的具体作用。
Rabbit hemorrhagic disease virus (RHDV) is a member of the Caliciviridae family (Lagovirus genus). RHDV is highly contagious and attaches to epithelial cells in the digestive or respiratory tract, leading to massive lesions with high mortality rates. A new variant of RHDV (termed RHDVb) recently has emerged, and previously vaccinated rabbits appear to have little protection against this new strain. Similar to human norovirus (Caliciviridae, Norovirus genus), RHDV binds histo-blood group antigens (HBGAs), and this is thought to be important for infection. Here, we report the HBGA binding site on the RHDVb capsid-protruding domain (P domain) using X-ray crystallography. The HBGA binding pocket was located in a negatively charged patch on the side of the P domain and at a dimeric interface. Residues from both monomers contributed to the HBGA binding and involved a network of direct hydrogen bonds and water-mediated interactions. An amino acid sequence alignment of different RHDV strains indicated that the residues directly interacting with the ABH-fucose of the HBGAs (Asp472, Asn474, and Ser479) were highly conserved. This result suggested that different RHDV strains also could bind HBGAs at the equivalent pocket. Moreover, several HBGA binding characteristics between RHDVb and human genogroup II norovirus were similar, which indicated a possible convergent evolution of HBGA binding interactions. Further structural studies with other RHDV strains are needed in order to better understand the HBGA binding mechanisms among the diverse RHDV strains.IMPORTANCEWe identified, for the first time, the HBGA binding site on an RHDVb P domain using X-ray crystallography. Our results showed that RHDVb and human genogroup II noroviruses had similar HBGA binding interactions. Recently, it was discovered that synthetic HBGAs or HBGA-expressing enteric bacteria could enhance human genogroup II norovirus infection in B cells. Considering that RHDVb and genogroup II norovirus similarly interacted with HBGAs, it may be possible that a comparable cell culture system also could work with RHDVb. Taken together, these new findings will extend our understanding of calicivirus HBGA interactions and may help to elucidate the specific roles of HBGAs in calicivirus infections.