Huang Sheng-Wen, Cheng Hui-Li, Hsieh Hsin-Yi, Chang Chia-Lun, Tsai Huey-Pin, Kuo Pin-Hwa, Wang Shih-Min, Liu Ching-Chuan, Su Ih-Jen, Wang Jen-Ren
Center of Infectious Disease and Signaling Research, National Cheng Kung University Hospital, Tainan, Taiwan.
J Biomed Sci. 2014 Apr 26;21(1):33. doi: 10.1186/1423-0127-21-33.
Clinical manifestations of enterovirus 71 (EV71) range from herpangina, hand-foot-and-mouth disease (HFMD), to severe neurological complications. Unlike the situation of switching genotypes seen in EV71 outbreaks during 1998-2008 in Taiwan, genotype B5 was responsible for two large outbreaks in 2008 and 2012, respectively. In China, by contrast, EV71 often persists as a single genotype in the population and causes frequent outbreaks. To investigate genetic changes in viral evolution, complete EV71 genome sequences were used to analyze the intra-genotypic evolution pattern in Taiwan, China, and the Netherlands.
Genotype B5 was predominant in Taiwan's 2008 outbreak and was re-emergent in 2012. EV71 strains from both outbreaks were phylogenetically segregated into two lineages containing fourteen non-synonymous substitutions predominantly in the non-structural protein coding region. In China, genotype C4 was first seen in 1998 and caused the latest large outbreak in 2008. Unlike shifting genotypes in Taiwan, genotype C4 persisted with progressive drift through time. A majority of non-synonymous mutations occurred in residues located in the non-structural coding region, showing annual increases. Interestingly, genotype B1/B2 in the Netherlands showed another stepwise evolution with dramatic EV71 activity increase in 1986. Phylogeny of the VP1 coding region in 1971-1986 exhibited similar lineage turnover with genotype C4 in China; however, phylogeny of the 3D-encoding region indicated separate lineage appearing after 1983, suggesting that the 3D-encoding region of genotype B2 was derived from an unidentified ancestor that contributed to intra-genotypic evolution in the Netherlands.
Unlike VP1 coding sequences long used for phylogenetic study of enteroviruses due to expected host immune escape, our study emphasizes a dominant role of non-synonymous mutations in non-structural protein regions that contribute to (re-)emergent genotypes in continuous stepwise evolution. Dozens of amino acid substitutions, especially in non-structural proteins, were identified via genetic changes driven through intra-genotypic evolution worldwide. These identified substitutions appeared to increase viral fitness in the population, affording valuable insights not only for viral evolution but also for prevention, control, and vaccine against EV71 infection.
肠道病毒71型（EV71）的临床表现范围从疱疹性咽峡炎、手足口病（HFMD）到严重的神经并发症。与1998 - 2008年台湾地区EV71疫情中出现的基因型转换情况不同，B5基因型分别在2008年和2012年引发了两次大规模疫情。相比之下，在中国，EV71通常以单一基因型在人群中持续存在并引发频繁疫情。为了研究病毒进化中的基因变化，完整的EV71基因组序列被用于分析台湾、中国内地和荷兰的基因型内进化模式。
B5基因型在台湾2008年的疫情中占主导地位，并在2012年再次出现。两次疫情中的EV71毒株在系统发育上被分为两个谱系，包含14个非同义替换，主要位于非结构蛋白编码区。在中国，C4基因型于1998年首次出现，并在2008年引发了最近一次大规模疫情。与台湾地区基因型的变化不同，C4基因型随着时间的推移持续存在并逐渐发生漂移。大多数非同义突变发生在非结构编码区的残基上，且呈逐年增加趋势。有趣的是，荷兰的B1/B2基因型呈现出另一种逐步进化的模式，1986年EV71的活性显著增加。1971 - 1986年VP1编码区的系统发育显示出与中国C4基因型相似的谱系更替；然而，3D编码区的系统发育表明1983年后出现了单独的谱系，这表明B2基因型的3D编码区源自一个未确定的祖先，该祖先促成了荷兰的基因型内进化。
与长期以来由于预期的宿主免疫逃逸而用于肠道病毒系统发育研究的VP1编码序列不同，我们的研究强调了非同义突变在非结构蛋白区域中的主导作用，这些突变在持续的逐步进化中促成了（重新）出现的基因型。通过全球范围内基因型内进化驱动的基因变化，鉴定出了数十个氨基酸替换，特别是在非结构蛋白中。这些鉴定出的替换似乎增加了病毒在人群中的适应性，不仅为病毒进化提供了有价值的见解，也为EV71感染的预防、控制和疫苗研发提供了依据。
