乙型肝炎病毒受体NTCP的进化揭示了灵长类动物，啮齿动物和

StephenW

Evolution of Hepatitis B Virus Receptor NTCP Reveals Differential Pathogenicities and Species Specificities of Hepadnaviruses in Primates, Rodents, and Bats
Stéphanie Jacquet, Jean-Baptiste Pons, Ariel De Bernardo, Barthélémy Ngoubangoye, François-Loic Cosset, Corinne Régis, Lucie Etienne, Dominique Pontier
J.-H. James Ou, Editor
DOI: 10.1128/JVI.01738-18

    ArticleFigures & DataInfo & Metrics
    PDF

ABSTRACT

Human hepatitis B virus (HBV) is a global health problem, affecting more than 250 million people worldwide. HBV-like viruses, named orthohepadnaviruses, also naturally infect nonhuman primates, rodents, and bats, but their pathogenicity and evolutionary history are unclear. Here, we determined the evolutionary history of the HBV receptors NTCP and GPC5 over millions of years of primate, rodent, and bat evolution. We use this as a proxy to understand the pathogenicity of orthohepadnaviruses in mammalian hosts and to determine the implications for species specificity. We found that NTCP, but not GPC5, has evolved under positive selection in primates (27 species), rodents (18 species), and bats (21 species) although at distinct residues. Notably, the positively selected codons map to the HBV-binding sites in primate NTCP, suggesting past genetic “arms races” with pathogenic orthohepadnaviruses. In rodents, the positively selected codons fall outside and within the presumed HBV-binding sites, which may contribute to the restricted circulation of rodent orthohepadnaviruses. In contrast, the presumed HBV-binding motifs in bat NTCP are conserved, and none of the positively selected codons map to this region. This suggests that orthohepadnaviruses may bind to different surfaces in bat NTCP. Alternatively, the patterns may reflect adaptive changes associated with metabolism rather than pathogens. Overall, our findings further point to NTCP as a naturally occurring genetic barrier for cross-species transmissions in primates, which may contribute to the narrow host range of HBV. In contrast, this constraint seems less important in bats, which may correspond to greater orthohepadnavirus circulation and diversity.

IMPORTANCE Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. Mammalian HBV-like viruses are also found in nonhuman primates, rodents, and bats. As for most viruses, HBV requires a successful interaction with a host receptor for replication. Cellular receptors are thus key determinants of host susceptibility as well as specificity. One hallmark of pathogenic virus-host relationships is the reciprocal evolution of host receptor and viral envelope proteins, as a result of their antagonistic interaction over time. The dynamics of these so-called “evolutionary arms races” can leave signatures of adaptive selection, which in turn reveal the evolutionary history of the virus-host interaction as well as viral pathogenicity and the genetic determinants of species specificity. Here, we show how HBV-like viruses have shaped the evolutionary history of their mammalian host receptor, as a result of their ancient pathogenicity, and decipher the genetic determinants of cross-species transmissions.

    Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

StephenW

乙型肝炎病毒受体NTCP的进化揭示了灵长类动物，啮齿动物和蝙蝠中嗜肝DNA病毒的差异致病性和物种特异性
StéphanieJacquet，Jean-Baptiste Pons，Ariel De Bernardo，BarthélémyNgoubangoye，François-Loic Cosset，CorinneRégis，Lucie Etienne，Dominique Pontier
J.-H. James Ou，编辑
DOI：10.1128 / JVI.01738-18

    ArticleFigures＆DataInfo＆Metrics
    PDF

抽象

人类乙型肝炎病毒（HBV）是一个全球性的健康问题，影响着全球超过2.5亿人。名为orthohepadnaviruses的HBV样病毒也自然感染非人类灵长类动物，啮齿动物和蝙蝠，但它们的致病性和进化史尚不清楚。在这里，我们确定了HBV受体NTCP和GPC5在数百万年的灵长类动物，啮齿动物和蝙蝠进化过程中的进化历史。我们使用它作为代理来了解哺乳动物宿主中的正嗜肝病毒的致病性并确定对物种特异性的影响。我们发现NTCP，但不是GPC5，在灵长类动物（27种），啮齿动物（18种）和蝙蝠（21种）的阳性选择中进化，尽管有不同的残基。值得注意的是，正选择的密码子映射到灵长类动物NTCP中的HBV结合位点，表明过去的遗传“武器种族”与致病性正嗜肝病毒。在啮齿动物中，阳性选择的密码子落在假定的HBV结合位点之外，这可能有助于啮齿动物的正嗜肝病毒的限制性循环。相比之下，蝙蝠NTCP中假定的HBV结合基序是保守的，并且没有一个正选择的密码子映射到该区域。这表明，正嗜肝炎病毒可以与蝙蝠NTCP中的不同表面结合。或者，模式可以反映与代谢相关的适应性变化而不是病原体。总体而言，我们的研究结果进一步指出NTCP是灵长类动物跨物种传播的天然遗传屏障，可能导致HBV宿主范围狭窄。相反，这种限制在蝙蝠中似乎不那么重要，这可能对应于更大的正嗜肝病毒循环和多样性。

重要性乙型肝炎病毒（HBV）的慢性感染是人类肝脏疾病和癌症的主要原因。在非人灵长类动物，啮齿动物和蝙蝠中也发现了哺乳动物HBV样病毒。对于大多数病毒，HBV需要与宿主受体成功相互作用以进行复制。因此，细胞受体是宿主易感性和特异性的关键决定因素。致病病毒 - 宿主关系的一个标志是宿主受体和病毒包膜蛋白的相互进化，这是它们随时间的拮抗相互作用的结果。这些所谓的“进化军备种族”的动态可以留下适应性选择的特征，这反过来揭示了病毒 - 宿主相互作用的进化历史以及病毒致病性和物种特异性的遗传决定因素。在这里，我们展示了HBV样病毒如何塑造其哺乳动物宿主受体的进化历史，这是由于它们具有古老的致病性，并且破译了跨物种传播的遗传决定因素。

    版权所有©2019美国微生物学会。

版权所有。