Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany.
J Hepatol. 2019 Jul;71(1):25-34. doi: 10.1016/j.jhep.2019.02.020. Epub 2019 Mar 13.
BACKGROUND & AIMS: Unlike other hepatitis viruses that have infected primates for millions of years, hepatitis A virus (HAV) likely entered human populations only 10-12 thousand years ago after jumping from a rodent host. The phylogeny of modern hepatoviruses that infect rodents and bats suggest that multiple similar host shifts have occurred in the past. The factors determining such shifts are unknown, but the capacity to overcome innate antiviral responses in a foreign species is likely key.
We assessed the capacity of diverse hepatovirus 3ABC proteases to cleave mitochondrial antiviral signaling protein (MAVS) and disrupt antiviral signaling in HEK293 and human hepatocyte-derived cell lines. We also applied maximum-likelihood and Bayesian algorithms to identify sites of diversifying selection in MAVS orthologs from 75 chiropteran, rodent and primate species.
3ABC proteases from bat, but not rodent hepatoviruses efficiently cleaved human MAVS at Glu/Gly, disrupting virus activation of the interferon-β promoter, whereas human HAV 3ABC cleaved at Gln/Val. In contrast, MAVS orthologs from rodents and bats were resistant to cleavage by 3ABC proteases of cognate hepatoviruses and in several cases human HAV. A search for diversifying selection among MAVS orthologs from all 3 orders revealed 90 of ∼540 residues to be under positive selection, including residues in chiropteran MAVS that align with the site of cleavage of human MAVS by bat 3ABC proteases.
3ABC protease cleavage of MAVS is a conserved attribute of hepatoviruses, acting broadly across different mammalian species and associated with evidence of diversifying selection at cleavage sites in rodent and bat MAVS orthologs. The capacity of hepatoviruses to disrupt MAVS-mediated innate immune responses has shaped evolution of both hepatoviruses and their hosts, and facilitates cross-species transmission of hepatitis A.
Hepatitis A virus, a common cause of acute hepatitis globally, is likely to have evolved from a virus that jumped from a rodent species to humans within the last 10-12 thousand years. Here we show that distantly related hepatoviruses, that infect bats and rodents today, express proteases that disrupt innate antiviral responses in human cells. This conserved attribute of hepatoviruses may have contributed to that ancient host species shift.
不同于其他已在灵长类动物中感染数百万年的肝炎病毒，甲型肝炎病毒（HAV）可能在 10-12 千年前从啮齿动物宿主跳跃到人类后才进入人类群体。感染啮齿动物和蝙蝠的现代肝炎病毒的系统发育表明，过去发生了多次类似的宿主转移。决定这些转移的因素尚不清楚，但在异源物种中克服先天抗病毒反应的能力可能是关键。
我们评估了来自不同肝炎病毒 3ABC 蛋白酶切割线粒体抗病毒信号蛋白（MAVS）和破坏 HEK293 和人肝细胞衍生细胞系中抗病毒信号的能力。我们还应用最大似然和贝叶斯算法来识别来自 75 种蝙蝠、啮齿动物和灵长类动物物种的 MAVS 直系同源物中的多样化选择位点。
来自蝙蝠的 3ABC 蛋白酶，但不是来自啮齿动物的肝炎病毒，有效地在 Glu/Gly 处切割人 MAVS，破坏病毒激活干扰素-β启动子，而人 HAV 3ABC 则在 Gln/Val 处切割。相比之下，来自啮齿动物和蝙蝠的 MAVS 直系同源物抵抗同源肝炎病毒和在几种情况下的人 HAV 的 3ABC 蛋白酶切割。对来自所有 3 个目 MAVS 直系同源物的多样化选择进行搜索，发现 540 个残基中的约 90 个处于正选择之下，包括蝙蝠 3ABC 蛋白酶切割人 MAVS 时与蝙蝠 MAVS 对齐的残基。
3ABC 蛋白酶切割 MAVS 是肝炎病毒的保守特征，在不同的哺乳动物物种中广泛作用，并与在啮齿动物和蝙蝠 MAVS 直系同源物的切割位点处的多样化选择证据相关。肝炎病毒破坏 MAVS 介导的先天免疫反应的能力塑造了肝炎病毒及其宿主的进化，并促进了甲型肝炎的跨物种传播。
全球范围内常见的急性肝炎病因甲型肝炎病毒可能是在过去 10-12 千年前从一种病毒跳跃到人类，这种病毒来源于啮齿动物。在这里，我们表明，今天感染蝙蝠和啮齿动物的远亲肝炎病毒表达的蛋白酶会破坏人类细胞中的先天抗病毒反应。肝炎病毒的这种保守特征可能促成了古代的宿主种间转移。
