1998-2011年中国肠道病毒71型的分子流行病学研究

发布时间：2018-07-08 14:37

本文选题：手足口病 + 监测　；参考：《中国疾病预防控制中心》2012年博士论文

【摘要】：自2008年以来,手足口病(hand, foot and mouth disease, HFMD)在我国大陆发生全国范围的大流行,成为危害婴幼儿健康的重要传染病。由此,HFMD于2008年5月2日开始,作为第38种法定报告传染病,纳入C类进行管理。同时开展全国范围的流行病学和病毒学监测。从国家法定传染病报告系统(National Notifiable Disease Reporting System, NNDRS)对发病时间为2008年1月1日至2011年12月31日的病例信息进行收集、整理和分析。数据显示2009-2011年,每年报告病例数为1,155,491-1,619,689例,其中具有神经体统症状的重症病例13,481-27,043例,死亡病例355-904例。1岁和2岁年龄组儿童具有最高的发病和死亡率,分别为(/10万)1,211-2,953和0.61-2.12。病毒学监测数据显示：EV71和CA16为主要的病原,而EV71感染在重症和死亡病例具有较高比例,分别占79%-82%和92%-95%。为了对流行的EV71的分子流行病学特征进行分析,本研究共测定或下载了(从GenBank)共3435株本土分离株的VP1全序列,以及129株的全基因组序列。采用生物信息学软件对序列进行分析。结果显示,C4亚型自1998年以来作为优势型别在我国大陆持续循环,其起源于～1994年,以4.6×10-3的速率不断进化。在不断进化中,C4分离株与SHZH98的进化距离随着流行年代逐渐增大。从2002-2004年,进化分支从C4b转化为了C4a。基于全基因组序列的分析结果显示,我国流行的EV71均与HEV-A组的其它EV发生型间重组。亲缘性和进化距离分析均表明：除P1以外的其它所有非结构区(P2、P3和UTR)均与HEV-A的其它EV发生了重组。虽然,重组发生部位和重组来源具有多样性,但大部分的流行株在基于各基因构建的亲缘性关系树上均相互聚为一簇,且相互间具有较小的进化距离(0.019-0.041)。提示：在我国大陆流行的C4亚型EV71为一群具有较高同源性的病毒。对各个基因进行的自然选择分析显示：EV71的整个基因组均处于负选择压力下,只有VP3的第93位密码子和VP1的第98位密码子为广泛存在的正选择位点。根据本研究得出的结果,我们认为：1)低年龄儿童,尤其是3岁以下婴幼儿是对HFMD进行预防和控制的重点目标人群；2)应对HFMD带来的健康威胁,重点应放在EV71；3)在持续传播过程中,C4亚型EV71通过点突变和基因重组的方式不断进化,但还需通过进一步的研究来阐述其在进化中是否获得了利于其传播的生物学性状;4)EV71基因组处于较强的负选择压力下,这将为EV71疫苗的研制提供便利。
[Abstract]:Since 2008, HFMD (hand, foot and mouth disease) has become a national epidemic in mainland China, and has become an important infectious disease endangering the health of infants and young children. HFMD, as the 38th legally reported infectious disease, was included in category C management since May 2, 2008. At the same time, epidemiological and virological surveillance was carried out nationwide. From the National Notifiable Disease reporting system (NNDRS), this paper collected, collated and analyzed the case information from January 1, 2008 to December 31, 2011. The data showed that 1155491-1619689 cases were reported every year in 2009-2011, of which 13481-27043 were severe cases with neurosomatic symptoms, 355-904 children aged 1. 1 years and 2 years old had the highest morbidity and mortality, respectively (1 / 100000) 1211-2953 and 0.61-2.12, respectively. Virological monitoring data showed that: EV71 and CA16 were the main pathogens, and EV71 infection had a higher proportion in severe cases and deaths, accounting for 79-82% and 92-9550%, respectively. In order to analyze the molecular epidemiological characteristics of EV71, the whole VP1 sequence of 3435 strains isolated from GenBank and the whole genome sequence of 129 strains were determined or downloaded in this study. The sequence was analyzed by bioinformatics software. The results show that the C _ 4 subtype has been circulating continuously in China continent since 1998, which originated from 1994 and evolved at a rate of 4.6 脳 10 ~ (-3). The evolutionary distance between C _ 4 isolate and SHZH98 gradually increased with the epidemic age. From 2002 to 2004, the evolutionary branch was transformed from C4b to C4a. The results based on the whole genome sequence showed that EV71 in China was recombined with other EV genomes in HEV-A group. Phylogenetic analysis and evolutionary distance analysis showed that all the non-structural regions (P2P3 and UTR) except P1 were recombined with other EV of HEV-A. Although the site and source of recombination are diverse, most of the prevalent strains are clustered into one cluster in the genetic tree based on each gene, and there is a small evolutionary distance between them (0.019-0.041). It is suggested that the C4 subtype EV71, which is prevalent in mainland China, is a group of viruses with high homology. The natural selection analysis of each gene showed that the whole genome of VEV71 was under negative selection pressure, and only the 93rd codon of VP3 and the 98th codon of VP1 were the ubiquitous positive selection sites. According to the results of this study, we think that low age children, especially children under 3 years old, are the key target population for HFMD prevention and control. 2) to deal with the health threat caused by HFMD, the emphasis should be on EV71. 3) during the process of continuous transmission, EV71 subtype C _ 4 evolved continuously through point mutation and gene recombination. However, further research is needed to explain whether the EV71 genome is under strong negative selection pressure, which will facilitate the development of EV71 vaccine.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R725.1

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