A Norovirus Uses Bile Salts To Escape Antibody Recognition While Enhancing Receptor Binding.
A Norovirus Uses Bile Salts To Escape Antibody Recognition While Enhancing Receptor Binding.
复制标题
诺如病毒利用胆汁盐逃避抗体识别，同时增强受体结合。
DOI：
10.1128/jvi.00176-21
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发表时间：
2021
影响因子：
5.4
通讯作者：
Smith,ThomasJ
中科院分区：
文献类型：
--
作者：
Williams,AlexisN;Sherman,MichaelB;Smith,HongQ;Taube,Stefan;Pettitt,BMontgomery;Wobus,ChristianeE;Smith,ThomasJ
诺如病毒是冠状病毒科的成员，是人类流行性肠胃炎的主要原因，每年造成约2000万例病例。这些正链RNA病毒具有T=3个二十面体蛋白衣壳和90个明显的突起(P)结构域二聚体，抗体和细胞受体可与之结合。在小鼠诺如病毒（MNV）的情况下，胆盐已被证明可以增强受体（CD300lf）与P结构域的结合。我们之前证明了几种基因型的P结构域具有明显的灵活性，并“漂浮”在壳上，但这种灵活性的作用尚不清楚。最近，我们证明了胆汁导致90°旋转和P结构域在壳表面的塌陷。由于胆汁在远端与p -壳界面结合，因此完全不清楚它是如何引起如此剧烈的变化的。在这里，我们展示了MNV突出结构域与中和Fab络合的近原子分辨率低温电镜（cryo-EM）结构。在先前结果的基础上，我们在这里表明胆盐引起P结构域的变构构象变化，从而阻断抗体对P结构域顶部的识别。此外，胆汁引起P结构域二聚体的重排，这可能是胆汁诱导的P结构域在壳上坍塌的原因。在收缩的壳构象中，P1和壳结构域的抗体预计不会结合。因此，在肠道感染部位，宿主自身的胆汁允许病毒逃避抗体介导的中和，同时增强细胞附着。杯状病毒衣壳的主要特征是90个突出结构域（P结构域），它们是细胞受体附着和抗体表位的位置。我们之前证明了这些P结构域是高度可移动的，胆汁导致小鼠诺如病毒（MNV）中的这些“浮动”P结构域收缩到外壳表面。在这里，我们展示了分离的MNV P结构域与中和的Fab片段络合的近原子低温电镜结构。我们的数据显示，胆汁会导致两组变化。首先，胆汁引起P结构域顶部表位的变构构象改变，从而阻断抗体结合。其次，胆汁导致P结构域二聚体亚基相互旋转，导致P结构域收缩，将表位埋在P结构域和壳结构域的底部。综上所述，结果表明MNV利用宿主自身代谢物增强细胞受体结合，同时阻断抗体识别。
Noroviruses, members of theCaliciviridaefamily, are the major cause of epidemic gastroenteritis in humans, causing ∼20 million cases annually. These plus-strand RNA viruses have T=3 icosahedral protein capsids with 90 pronounced protruding (P) domain dimers to which antibodies and cellular receptors bind. In the case of mouse norovirus (MNV), bile salts have been shown to enhance receptor (CD300lf) binding to the P domain. We demonstrated previously that the P domains of several genotypes are markedly flexible and “float” over the shell, but the role of this flexibility was unclear. Recently, we demonstrated that bile causes a 90° rotation and collapse of the P domain onto the shell surface. Since bile binds distally to the P–shell interface, it was not at all clear how it could cause such dramatic changes. Here, we present the near-atomic resolution cryo-electron microscopy (cryo-EM) structure of the MNV protruding domain complexed with a neutralizing Fab. On the basis of previous results, we show here that bile salts cause allosteric conformational changes in the P domain that block antibody recognition of the top of the P domain. In addition, bile causes a major rearrangement of the P domain dimers that is likely responsible for the bile-induced collapse of the P domain onto the shell. In the contracted shell conformation, antibodies to the P1 and shell domains are not expected to bind. Therefore, at the site of infection in the gut, the host’s own bile allows the virus to escape antibody-mediated neutralization while enhancing cell attachment.IMPORTANCEThe major feature of calicivirus capsids is the 90 protruding domains (P domains) that are the site of cell receptor attachment and antibody epitopes. We demonstrated previously that these P domains are highly mobile and that bile causes these “floating” P domains in mouse norovirus (MNV) to contract onto the shell surface. Here, we present the near-atomic cryo-EM structure of the isolated MNV P domain complexed with a neutralizing Fab fragment. Our data show that bile causes two sets of changes. First, bile causes allosteric conformational changes in the epitopes at the top of the P domain that block antibody binding. Second, bile causes the P domain dimer subunits to rotate relative to each other, causing a contraction of the P domain that buries epitopes at the base of the P and shell domains. Taken together, the results show that MNV uses the host’s own metabolites to enhance cell receptor binding while simultaneously blocking antibody recognition.