Hepadnaviruses诱导的牛磺胆酸钠协同转运多肽中的单一自适应突

StephenW

A Single Adaptive Mutation in Sodium Taurocholate Cotransporting Polypeptide Induced by Hepadnaviruses Determines Virus Species Specificity
Junko S. Takeuchi, Kento Fukano, Masashi Iwamoto, Senko Tsukuda, Ryosuke Suzuki, Hideki Aizaki, Masamichi Muramatsu, Takaji Wakita, Camille Sureau, Koichi Watashi
J.-H. James Ou, Editor
DOI: 10.1128/JVI.01432-18

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ABSTRACT

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 NTCP-encoding 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); this observation implies that the evolution of NTCP is restricted by maintaining its original protein function. However, 0.7% of NTCP amino acid residues exhibit rapid evolution under positive selection (dN/dS ratio of >1). Notably, a substitution at amino acid (aa) 158, a positively selected residue, converting the human NTCP to a monkey-type 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 hepadnaviruses 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.

    Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

StephenW

Hepadnaviruses诱导的牛磺胆酸钠协同转运多肽中的单一自适应突变决定病毒种类的特异性
Junko S. Takeuchi，Kento Fukano，Masashi Iwamoto，Senko Tsukuda，Ryosuke Suzuki，Hideki Aizaki，Masamichi Muramatsu，Takaji Wakita，Camille Sureau，Koichi Watashi
J.-H. James Ou，编辑
DOI：10.1128 / JVI.01432-18

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抽象

乙型肝炎病毒（HBV）及其嗜肝DNA病毒亲属感染广泛的脊椎动物，从鱼类到人类。嗜肝DNA病毒及其宿主在获得适应性突变方面有着悠久的历史。然而，没有报道为嗜肝DNA病毒与其寄主之间的这种共同进化的“军备竞赛”提供直接的分子证据。在这里，我们提出的证据表明牛磺胆酸钠协同转运多肽（NTCP）（一种HBV受体）的适应性进化受到病毒感染的影响。来自20个哺乳动物的NTCP编码基因的进化分析表明，大多数NTCP残基在物种中高度保守，在负选择下表现出进化（dN / dS比率[非同义与同义进化变化的比率] <1）;这一观察意味着NTCP的进化受到维持其原始蛋白质功能的限制。然而，0.7％的NTCP氨基酸残基在阳性选择下表现出快速进化（dN / dS比率> 1）。值得注意的是，氨基酸（aa）158的取代，一个正选择的残基，将人NTCP转化为猴型序列，废除了支持HBV感染的能力;相反，在该残基处将猴Ntcp转化为人序列的取代足以赋予HBV易感性。总之，这些观察结果表明aa 158阳性选择与病毒感染的压力密切相关。此外，aa 158序列确定了HBV包膜蛋白与宿主细胞的附着，证明了HBV感染将在该NTCP残基处产生阳性选择的机制。总之，我们提供的第一个证据与嗜肝DNA病毒作为诱导宿主受体适应性突变的驱动因子的功能一致。

重要性HBV及其嗜肝DNA病毒亲属感染广泛的脊椎动物，具有悠久的传染病史（数亿年）。如此悠久的历史通常允许宿主中的适应性突变逃避感染，同时允许病毒中的适应性突变以克服宿主屏障。然而，在嗜肝DNA病毒和宿主之间没有公开的分子证据表明这种共同进化的军备竞赛。在本研究中，我们进行了嗜肝DNA病毒和牛磺胆酸钠协同转运多肽（NTCP）（HBV受体）之间的共同进化系统发育分析，并结合病毒学实验分析来研究NTCP序列变异的生物学意义。我们的数据提供了支持HBV相关嗜肝DNA病毒在NTCP序列中推动适应性进化的第一个分子证据，包括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嗜肝DNA病毒如何与宿主进化的理解，从而获得了强大的物种特异性。

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