Amino acid substitutions in norovirus VP1 dictate host dissemination via variations in cellular attachment.
Amino acid substitutions in norovirus VP1 dictate host dissemination via variations in cellular attachment.
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DOI：
10.1128/jvi.01719-23
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发表时间：
2023-12-21
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
--
作者：
病毒与细胞表面的受体相互作用以启动和协调感染。受体在宿主细胞上的分布可以是病毒嗜性和宿主感染的关键决定因素。因此，揭示病毒-受体相互作用的复杂本质对于理解病毒的发病机制至关重要。诺如病毒是对人类健康具有全球重要性的无包膜、二十面体、正义RNA病毒，没有批准的疫苗或抗病毒剂可用。在这里，我们使用鼠诺如病毒作为模型来研究病毒-受体相互作用的分子机制。我们发现，在一个主要的病毒衣壳蛋白，VP 1 301，在一个单一的氨基酸残基的变化，病毒和受体之间的相互作用有着关键的影响。这种变异不影响病毒体复制或病毒生长动力学，但通过进化实验快速选择了特定的氨基酸，并在感染悬浮细胞时显著改善了细胞附着。然而，调节质膜流动性抵消了这种表型，表明膜流动性在诺如病毒细胞附着中的作用。当在体内比较在该残基处具有单个氨基酸取代的一组重组病毒的感染性时，病毒在鼠宿主中的组织分布存在差异，表明VP 1 301在体内传播中的作用。总的来说，这些结果突出了衣壳进化如何影响宿主中的感染性和传播。所有病毒通过利用受体附着到靶宿主细胞来启动感染。因此，这些病毒-受体相互作用可以决定病毒复制和发病机制。了解病毒-受体相互作用的性质对于开发新疗法也很重要。诺如病毒是具有医学重要性的无包膜二十面体病毒。它们是急性胃肠炎的常见原因，没有批准的疫苗或治疗方法，并且是研究基础病毒生物学的易处理模型。在这项研究中，我们利用鼠诺如病毒模型系统，以表明，在一个单一的氨基酸的主要衣壳蛋白的变化，单独可以影响病毒的感染性，通过改善附着到悬浮细胞。调节质膜流动性降低了感染性，表明膜流动性对受体募集和/或受体构象的重要性。此外，在该位点的不同取代改变了小鼠模型中的病毒组织分布，说明了宿主衣壳进化如何影响病毒感染性和/或免疫逃避。
Viruses interact with receptors on the cell surface to initiate and coordinate infection. The distribution of receptors on host cells can be a key determinant of viral tropism and host infection. Unravelling the complex nature of virus-receptor interactions is, therefore, of fundamental importance to understanding viral pathogenesis. Noroviruses are non-enveloped, icosahedral, positive-sense RNA viruses of global importance to human health, with no approved vaccine or antiviral agent available. Here, we use murine norovirus as a model to study the molecular mechanisms of virus-receptor interactions. We show that variation at a single amino acid residue in the major viral capsid protein, VP1 301, has a key impact on the interaction between virus and receptor. This variation did not affect virion replication or virus growth kinetics, but a specific amino acid was rapidly selected through evolution experiments and significantly improved cellular attachment when infecting cells in suspension. However, modulating plasma membrane mobility counteracted this phenotype, suggesting a role for membrane fluidity in norovirus cellular attachment. When the infectivity of a panel of recombinant viruses with single amino acid substitutions at this residue was compared in vivo, there were differences in the tissue distribution of viruses in a murine host, suggesting a role for VP1 301 in dissemination in vivo. Overall, these results highlight how capsid evolution can influence infectivity and dissemination in the host. All viruses initiate infection by utilizing receptors to attach to target host cells. These virus-receptor interactions can therefore dictate viral replication and pathogenesis. Understanding the nature of virus-receptor interactions could also be important for the development of novel therapies. Noroviruses are non-enveloped icosahedral viruses of medical importance. They are a common cause of acute gastroenteritis with no approved vaccine or therapy and are a tractable model for studying fundamental virus biology. In this study, we utilized the murine norovirus model system to show that variation in a single amino acid of the major capsid protein alone can affect viral infectivity through improved attachment to suspension cells. Modulating plasma membrane mobility reduced infectivity, suggesting an importance of membrane mobility for receptor recruitment and/or receptor conformation. Furthermore, different substitutions at this site altered viral tissue distribution in a murine model, illustrating how in-host capsid evolution could influence viral infectivity and/or immune evasion.
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DOI：
10.3390/v13112162
发表时间：
2021-10-26
期刊：
Viruses
影响因子：
--
作者：
Sherman MB;Williams AN;Smith HQ;Pettitt BM;Wobus CE;Smith TJ
通讯作者：
Smith TJ
影响因子：
7.3
作者：
通讯作者：
--
影响因子：
6.7
作者：
Herod MR;Gold S;Lasecka-Dykes L;Wright C;Ward JC;McLean TC;Forrest S;Jackson T;Tuthill TJ;Rowlands DJ;Stonehouse NJ
通讯作者：
Stonehouse NJ
影响因子：
3.7
作者：
Hanaki K;Ike F;Kajita A;Yasuno W;Yanagiba M;Goto M;Sakai K;Ami Y;Kyuwa S
通讯作者：
Kyuwa S
影响因子：
5.4
作者：
Gonzalez-Hernandez, Mariam B.;Liu, Thomas;Wobus, Christiane E.
通讯作者：
Wobus, Christiane E.