Drexler Jan Felix, Corman Victor M, Lukashev Alexander N, van den Brand Judith M A, Gmyl Anatoly P, Brünink Sebastian, Rasche Andrea, Seggewiβ Nicole, Feng Hui, Leijten Lonneke M, Vallo Peter, Kuiken Thijs, Dotzauer Andreas, Ulrich Rainer G, Lemon Stanley M, Drosten Christian
Institute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany; German Centre for Infection Research, Bonn-Cologne, Germany;
Chumakov Institute of Poliomyelitis and Viral Encephalitides, Moscow 142782, Russia;
Proc Natl Acad Sci U S A. 2015 Dec 8;112(49):15190-5. doi: 10.1073/pnas.1516992112. Epub 2015 Nov 2.
Hepatitis A virus (HAV) is an ancient and ubiquitous human pathogen recovered previously only from primates. The sole species of the genus Hepatovirus, existing in both enveloped and nonenveloped forms, and with a capsid structure intermediate between that of insect viruses and mammalian picornaviruses, HAV is enigmatic in its origins. We conducted a targeted search for hepatoviruses in 15,987 specimens collected from 209 small mammal species globally and discovered highly diversified viruses in bats, rodents, hedgehogs, and shrews, which by pairwise sequence distance comprise 13 novel Hepatovirus species. Near-complete genomes from nine of these species show conservation of unique hepatovirus features, including predicted internal ribosome entry site structure, a truncated VP4 capsid protein lacking N-terminal myristoylation, a carboxyl-terminal pX extension of VP1, VP2 late domains involved in membrane envelopment, and a cis-acting replication element within the 3D(pol) sequence. Antibodies in some bat sera immunoprecipitated and neutralized human HAV, suggesting conservation of critical antigenic determinants. Limited phylogenetic cosegregation among hepatoviruses and their hosts and recombination patterns are indicative of major hepatovirus host shifts in the past. Ancestral state reconstructions suggest a Hepatovirus origin in small insectivorous mammals and a rodent origin of human HAV. Patterns of infection in small mammals mimicked those of human HAV in hepatotropism, fecal shedding, acute nature, and extinction of the virus in a closed host population. The evolutionary conservation of hepatovirus structure and pathogenesis provide novel insight into the origins of HAV and highlight the utility of analyzing animal reservoirs for risk assessment of emerging viruses.
甲型肝炎病毒（HAV）是一种古老且广泛存在的人类病原体，此前仅从灵长类动物中分离得到。作为肝炎病毒属的唯一物种，HAV以包膜和非包膜两种形式存在，其衣壳结构介于昆虫病毒和哺乳动物小核糖核酸病毒之间，起源成谜。我们在全球209种小型哺乳动物的15987份样本中进行了针对性的肝炎病毒搜索，在蝙蝠、啮齿动物、刺猬和鼩鼱中发现了高度多样化的病毒，通过两两序列距离分析，这些病毒构成了13个新的肝炎病毒物种。其中9个物种的近乎完整基因组显示出独特的肝炎病毒特征的保守性，包括预测的内部核糖体进入位点结构、缺乏N端肉豆蔻酰化的截短VP4衣壳蛋白、VP1的羧基端pX延伸、参与膜包裹的VP2晚期结构域以及3D（pol）序列中的顺式作用复制元件。一些蝙蝠血清中的抗体能够免疫沉淀并中和人类HAV，表明关键抗原决定簇具有保守性。肝炎病毒与其宿主之间有限的系统发育共分离和重组模式表明，过去肝炎病毒的宿主发生了重大转移。祖先状态重建表明，肝炎病毒起源于小型食虫哺乳动物，而人类HAV起源于啮齿动物。小型哺乳动物的感染模式在嗜肝性、粪便排毒、急性性质以及封闭宿主群体中病毒的灭绝方面与人类HAV相似。肝炎病毒结构和发病机制的进化保守性为HAV的起源提供了新的见解，并突出了分析动物宿主库以评估新兴病毒风险的实用性。
