Functional and structural characterization of Norovirus GII.6 in recognizing histo-blood group antigens

Xin Cong; Han-bo Li; Xiao-man Sun; Jian-xun Qi; Qing Zhang; Zhao-jun Duan; Yong Xu; Wen-lan Liu

doi:10.1016/j.virs.2022.09.010

February 2023

. doi: 10.1016/j.virs.2022.09.010

Citation: Xin Cong, Han-bo Li, Xiao-man Sun, Jian-xun Qi, Qing Zhang, Zhao-jun Duan, Yong Xu, Wen-lan Liu. Functional and structural characterization of Norovirus GII.6 in recognizing histo-blood group antigens .VIROLOGICA SINICA, 2023, 38(1) : 56-65. http://dx.doi.org/10.1016/j.virs.2022.09.010

GII.6诺如病毒识别组织血型抗原的功能和结构基础

丛鑫 ^a,b ,
李涵博 ^c,d ,
孙晓曼 ^c,d ,
齐建勋 ^e ,
章青 ^c,d ,
段招军 ^c,d,, ,
徐勇 ^b,, ,
刘文兰 ^a,b,,

1 深圳市第二人民医院/深圳大学医学部第一附属医院神经外科, 深圳, 518035;
2 深圳市第二人民医院/深圳大学医学部第一附属医院医学遗传学与分子诊断中心, 深圳, 518035, 中国;
3 中华人民共和国国家卫生健康委员会医学病毒学与病毒性疾病重点实验室, 北京 102206;
4 中国疾病预防控制中心病毒病预防控制所, 北京 102206;
5 中国科学院微生物研究所, 北京 100101

通讯作者： 段招军, zhaojund@126.com; 徐勇, xuyong_2000@tom.com; 刘文兰, wlliu@szu.edu.cn
收稿日期： 2022-01-24
录用日期： 2022-07-04

摘要

诺如病毒（NoVs）是引起全球急性肠胃炎的主要病因。组织血型抗原（HBGAs）是影响诺如病毒流行和宿主易感性的受体或附着因子。GII.6 NoV是人类的流行的基因型别之一，识别HBGAs的ABO分泌型。然而，GII.6 NoV与HBGAs受体相互作用的结构基础仍不清楚。在本研究中，我们利用唾液和聚糖的酶联免疫吸附试验研究了GII.6与HBGAs的结合特征，确定了GII.6识别H双糖的分子基础。结果表明，GII.6 P区蛋白能够识别部分A、O分泌型唾液样本、大部分B分泌型唾液样本以及H双糖抗原，但不能与非分泌型唾液结合。然后，我们测定了GII.6及其H双糖复合物晶体结构，分辨率均为1.7 Å，揭示了GII.6的P区蛋白具有GII HBGAs的传统结合表面和结合模式。对GII.6与H结合位点的单个氨基酸进行突变，可以抑制GII.6与HBGAs的结合，这表明相互作用氨基酸在维持诺如病毒和寡糖相互作用的完整性方面起着至关重要的作用。最后，结构和序列分析表明GII.6-H互作的主要氨基酸在GII基因群中是保守的。综上所述，我们的研究明确了GII.6与HBGAs相互作用的功能和结构特征，，并对诺如病毒的进化、流行病学和抗病毒药物的研发提供了基础。
- 诺如病毒
- , 组织血型抗原
- , GII,6 P蛋白的结构
- , H双糖

Functional and structural characterization of Norovirus GII.6 in recognizing histo-blood group antigens

Xin Cong ^a,b ,
Han-bo Li ^c,d ,
Xiao-man Sun ^c,d ,
Jian-xun Qi ^e ,
Qing Zhang ^c,d ,
Zhao-jun Duan ^c,d,, ,
Yong Xu ^b,, ,
Wen-lan Liu ^a,b,,

a. Department of Neurosurgery, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518035, China;
b. The Center for Medical Genetics & Molecular Diagnosis, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, 518035, China;
c. Key Laboratory for Medical Virology and Viral Diseases, National Health Commission of the People's Republic of China, Beijing, 102206, China;
d. National Institute for Viral Disease Control and Prevention, China CDC, Beijing, 102206, China;
e. Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China

Corresponding author: Zhao-jun Duan, zhaojund@126.com Yong Xu, xuyong_2000@tom.com Wen-lan Liu, wlliu@szu.edu.cn
Received Date: 24 January 2022
Accepted Date: 04 July 2022

Abstract

Noroviruses (NoVs) are the primary cause of acute gastroenteritis worldwide. Histo-blood group antigens (HBGAs) are receptors or attachment factors that affect the prevalence and host susceptibility of NoVs. GII.6 NoV is one of the predominant genotypes in humans, which recognizes the type ABO secretor of HBGAs. However, the structural basis of GII.6 NoV's interaction with HBGAs receptors remains elusive. In this study, we investigated the binding features of the GII.6 strain to HBGAs using saliva- and glycan-ELISA assays and characterized the molecular basis of the GII.6 virus that recognizes H disaccharide. We showed that the GII.6 P domain recognized some A and O secretor's saliva samples, most B secretor's saliva samples, and H disaccharide antigen, but did not bind non-secretors' saliva. Further, we determined the crystal structures of GII.6 and its complex with H disaccharides at 1.7 Å, revealing that the P domain of GII.6 shares the conventional binding interface and mode of GII HBGAs. Single residue mutations at the GII.6-H binding sites could inhibit the binding of GII.6 to HBGAs, demonstrating that the interaction residues were crucial in maintaining NoV-glycan integrity. Finally, structural and sequence analyses showed that the major residues of the GII.6-H interaction were conserved among NoVs in the GII genogroup. Taken together, our study characterized the functional and structural features of GII.6 that allow it to interact with HBGAs, and shed light on NoV evolution, epidemiology, and anti-viral drug development.
- Noroviruses (NoVs)
- , Histo-blood group antigens (HBGAs)
- , GII.6 P protein structure
- , H disaccharides

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