A Single Adaptive Mutation in Sodium Taurocholate Cotransporting Polypeptide Induced by Hepadnaviruses Determines Virus Species Specificity
A Single Adaptive Mutation in Sodium Taurocholate Cotransporting Polypeptide Induced by Hepadnaviruses Determines Virus Species Specificity
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DOI：
10.1128/jvi.01432-18
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发表时间：
2019-03-01
影响因子：
5.4
通讯作者：
Watashi, Koichi
中科院分区：
文献类型：
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作者：
Takeuchi, Junko S.;Fukano, Kento;Watashi, Koichi
从鱼到人，各种脊椎动物都感染了乙肝病毒(乙肝病毒)及其近亲。肝炎病毒及其宿主获得适应性突变的历史由来已久。然而，还没有报告提供直接的分子证据来证明庚型核糖核酸病毒和它们的宿主之间存在这种共同进化的“军备竞赛”。在这里，我们提出的证据表明，牛磺胆酸钠共转运多肽(NTCP)，一种乙肝病毒受体，其适应性进化已受到病毒感染的影响。对20种哺乳动物的NTCP编码基因的进化分析表明，大多数NTP残基在物种之间高度保守，表现出负选择下的进化(dN/ds比率[非同义与同义进化变化的比率]为1)。值得注意的是，氨基酸(AA)158位的替换将人NtCP转换为猴型序列，使其丧失了支持乙肝病毒感染的能力；相反，将猴子Ntcp转换为人序列的该残基的替换足以赋予乙肝病毒易感性。综上所述，这些观察结果表明，AA 158阳性选择与病毒感染带来的压力密切相关。此外，aa158序列决定了乙肝病毒包膜蛋白与宿主细胞的结合，这表明了乙肝病毒感染将在这个NTCP残基上产生正选择的机制。总之，我们提供了第一个证据，证实了肝炎病毒作为驱动因素在宿主受体中诱导适应性突变的功能。重要的是，乙肝病毒及其近亲感染了广泛的脊椎动物，具有悠久的感染历史(数亿年)。如此漫长的病史通常允许宿主中的适应性突变逃脱感染，同时允许病毒中的适应性突变克服宿主屏障。然而，还没有公开发表的分子证据表明庚型核糖核酸病毒和宿主之间存在这种共同进化的军备竞赛。在本研究中，我们结合病毒学实验方法，对肝炎病毒和乙肝病毒受体牛磺胆酸钠共转运多肽(NTCP)进行了共同进化的系统发育分析，以探讨NTCP序列变异的生物学意义。我们的数据提供了第一个分子证据，支持乙肝病毒相关的Hepadna病毒驱动NTCP序列的适应性进化，包括对NTCP突变如何决定宿主病毒易感性的机制解释。我们的新见解增强了我们对庚型核糖核酸病毒如何与宿主一起进化的理解，从而使我们能够获得强大的物种特异性。
Hepatitis B virus (HBV) and its hepadnavirus relatives infect a wide range of vertebrates, from fish to human. Hepadnaviruses and their hosts have a long history of acquiring adaptive mutations. However, there are no reports providing direct molecular evidence for such a coevolutionary " arms race" between hepadnaviruses and their hosts. Here, we present evidence suggesting that the adaptive evolution of the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, has been influenced by virus infection. Evolutionary analysis of the NTCPencoding genes from 20 mammals showed that most NTCP residues are highly conserved among species, exhibiting evolution under negative selection (dN/dS ratio [ ratio of nonsynonymous to synonymous evolutionary changes] of 1). Notably, a substitution at amino acid (aa) 158, a positively selected residue, converting the human NTCP to a monkeytype sequence abrogated the capacity to support HBV infection; conversely, a substitution at this residue converting the monkey Ntcp to the human sequence was sufficient to confer HBV susceptibility. Together, these observations suggested a close association of the aa 158 positive selection with the pressure by virus infection. Moreover, the aa 158 sequence determined attachment of the HBV envelope protein to the host cell, demonstrating the mechanism whereby HBV infection would create positive selection at this NTCP residue. In summary, we provide the first evidence in agreement with the function of hepadnavirus as a driver for inducing adaptive mutation in host receptor.IMPORTANCE HBV and its hepadnavirus relatives infect a wide range of vertebrates, with a long infectious history (hundreds of millions of years). Such a long history generally allows adaptive mutations in hosts to escape from infection while simultaneously allowing adaptive mutations in viruses to overcome host barriers. However, there is no published molecular evidence for such a coevolutionary arms race between hepadnaviruses and hosts. In the present study, we performed coevolutionary phylogenetic analysis between hepadnaviruses and the sodium taurocholate cotransporting polypeptide (NTCP), an HBV receptor, combined with virological experimental assays for investigating the biological significance of NTCP sequence variation. Our data provide the first molecular evidence supporting that HBV-related hepadna-viruses drive adaptive evolution in the NTCP sequence, including a mechanistic explanation of how NTCP mutations determine host viral susceptibility. Our novel insights enhance our understanding of how hepadnaviruses evolved with their hosts, permitting the acquisition of strong species specificity.