中国大陆引起手足口病柯萨奇病毒A组4型基因特征分析
发布时间：2018-08-31 20:43
【摘要】：[背景]人类肠道病毒(Human Enterovirus, HEV)属于小核糖核酸病毒科(Picornavirdae)肠道病毒(Enterovirus)属,目前已经报道了119个血清型,被分为EV-A、EV-B、EV-C和EV-D共4组。多数情况下,HEV感染的病人是无症状的,或者只引起轻微症状,如发热、皮疹、或轻微上呼吸道症状；但有时HEV感染也可以引起广泛多样的临床疾病,如急性出血性结膜炎、无菌性脑膜炎、急性弛缓性麻痹(Acute Flaccid Paralysis, AFP)、手足口病(Hand, Foot and Mouth Disease、心肌炎、类感冒病症等。近年来,由HEV引起的各类疾病一直旱.现上升趋势。HEV病毒的基因组为单股正链RNA,长约7.5kb,整个基因组只含有一个开放阅读框架(Open Reading Frame, ORF),编码一个多聚蛋白(Polyprotein),最后水解产生VP1-VP4共4个结构蛋白和7个非结构蛋白。其中VP1蛋白是最主要的衣壳蛋白,是HEV与宿主细胞上受体进行识别、结合的主要结构,包含重要的血清型特异性中和位点；VP1蛋白位于病毒颗粒的最外表而,在机体免疫压力下,会发生变异而形成不同的流行株。因此,对VPl蛋白核苷酸序列的研究,不仅可以确定HEV的血清型别,而且可以说明病毒核酸之间同源性的大小,从而明确病毒进化变异的方向及其传播链。手足口病是多种肠道病毒(EV)引起的常见传染病。自中国大陆地区在2007年出现HFMD的爆发流行后,手足口病渐渐受到关注,据近年来的相关文献报道看,中国大陆手足口病的疫情有愈演愈烈的倾向,HFMD已经成为严重威胁广大人群特别是儿童身体健康与生命安全的重大公共卫生问题之一。EV71和CA16是引起HFMD的主要病原体,对手足口病病原学的研究多也集中在EV71和CA16,对其他肠道病毒的研究相对较少,在但近年来,一些地区的HFMD监测数据表明,其他型肠道病毒的病原构成比例有所升高,CVA4就是其中之一。本研究针对2008-2012年中国大陆地区HF-MI)病例中分离的CVA4毒株VPI编码区和3D区基因特征,开展分子流行分析。[目的]通过对2008-2012年中国大陆地区HFMD病例中的CVA4毒株VP1和3D基因特征进行系统性的分析,阐明其在我国的基因变异变迁规律。丰富我国和世界上CVA4的毒株库和基因信息库,为我国CVA4引起的HFMD的诊断、预防和控制提供科学支持。[研究方法]1.毒株来源：2012年江苏省赣榆县的1246份HFMD、病毒性脑炎、疱疹性咽峡炎临床标本分离的CVA4病毒57株；2008-2012年中国大陆HFMD监测网络实验室在其他地区HFMD病例中分离到19株CVA4。2.基因测序：提取病毒RNA, RT-PCR扩增VP1和3D区基因全长,并对PCR产物进行序列测定。3.生物信息学分析：采用BioEdit Sequence Alignment Editor software 7.0软件对本研究CVA4的VP1和3D基因与GenBank中检索到的中国及其它国家和地区的CVA4的VP1和3D基因进行核苷酸序列进行同源性比较,并对VP1基因核苷酸的基因变异所提示的氨基酸序列变异进行对比分析。使用Mega5.0软件,以相邻连接方法(Neighbor-joining Method)构建VP1区和3D区系统进化树,进行亲缘性和进化分析。[结果]1.江苏省赣榆县HFMD、病毒性脑炎、疱疹性咽峡炎等临床标本共分离到350株毒株,其中CVB3(142株)、CVA4(57株),CVA10(31株)、CVA16(29株)、EV71(24株)等。CVA4排第二位,所占比例为16%。赣榆县分离到的57株CVA4毒株VP1 5’端564个核苷酸序列同源性为94.0%-100%,氨基酸序列同源性为97.8%-100%,选取2株做VPl编码区基因915个核苷酸的序列测定。2.中国大陆分离到的21株CVA4代表株的VP1区序列相互间核苷酸序列的同源性为94.1%-100%,氨基酸序列同源性为97.3%-100%,同源性较高,进化关系密切。3.本次研究获得的2008-2012年21株CVA4代表株VP1序列和在GenBank中获得分离于中国大陆的10株CVA4的VP1序列做同源性分析：中国大陆分离到的31株CVA4的VP1区编码区基因的同源性在85.5%-100%之间,氨基酸序列同源性为97.5%-100%,同源性较高,属于同一个基因型,核苷酸的突变多为同义突变；1998年分离于山东省AFP病例的两株CVA4与其他年份分离的毒株核苷酸序列同源性在88.5%-89.9%,序列差异较大。排除1998年分离株,其余HFMD与AFP分离株之间的核苷酸序列同源性为94.8%,氨基酸序列同源性为98.4%,核苷酸和氨基酸在2种病例类型中未见特异差异何点；HFMD轻症和重症病例分离株之间的核苷酸序列同源性为95.5%,氨基酸序列同源性为98.8%,核苷酸和氨基酸在HFMD的2种病例类型中也未见特异差异位点。4.本次研究获得的21株CVA4代表株VP1序列和在GenBank中获得全球21株CVA4的VP1序列做亲缘进化树：基于国际肠道病毒基因型分型标准,依据VP1区编码基因全长可以将CVA4划分为5个基因型,分别为A、B、C、D、E基因型；这是首次基于VP1基因全长对CVA4进行基因型的划分。各基因型毒株核苷酸序列组间遗传距离为14.5%-26.7%,组内遗传距离为2.0%-3.5%。分离于中国大陆的31株CVA4病毒都属于E基因型,E基因型又被划分为E1和E2基因亚型,其中E1基因亚型包括1998年分离于山东AFP病例的2株毒株和2006年分离于吉林省AFP病例的1株毒株：E2基因亚型包括了2008-2012年分离于HFMD病例的22株CVA4毒株,以及2006-2008年分离于山东省和吉林省AFP病例的6株毒株。E1和E2基因亚型毒株组间的核苷酸序列平均遗传距离为12.6%,可见在中国大陆至少存在两条大的传播链,2006年及以前以E1基因亚型流行为主,2006以后以E2基因亚型流行为主。GenBank中CVA4的VP1区3’端的序列信息较VP1区全长更为丰富,将本次研究获得的21株CVA4毒株VP1区3’端420个核苷酸序列和在GenBank中获得44株CVA4的VP1区3’端序列代表株做亲缘进化树：基于VP1区3’端420个核苷酸序列,CVA4毒株可以划分为5个进化分支,分别为Lineage A～E。各Lineage毒株核苷酸序列组间遗传距离为13.4%-26.1%,组内遗传距离为5.8%-9.6%。其进化分支与以VP1区基因全长所做进化树结果相符,基因型A～E所包括毒株与对应各Lineage A～E毒株相一致。分离于中国大陆的31株CVA4病毒都属于Lineage E, Lineage E同样可以分为Lineage E1和Lineage E2,并且和VP1全长划分的结果也一致,Lineage E除包括中国大陆的毒株外,还包括分离于台湾的毒株。57株分离于江苏赣榆县的CVA4毒株,基于5’端的序列测定提示全部为E2基因亚型。5.选取5株CVA4代表毒株完成3D区序列的测定,并与其他可以检索到的CVA4、HEV-A组所有肠道病毒原型株、BLAST后同源性较高的毒株和EV71 C4a基因亚型代表株的3D区序列进行基因同源性比较并构建亲缘进化树：5株CVA4毒株和2009年分离于中国深圳的CVA4毒株(HQ728260)和2009年分离于广东省的EV71毒株(JF 799986)在一个进化分支上,序列同源性高达94.6%-96%；这株EV71与EV71的原型株BrCr株或其他EV71 C4a基因亚型的代表株遗传距离较远,序列同源性只有73.3%-81.7%,推测这一株EV71病毒的3D区可能来源于与中国大陆流行的CVA4的3D区重组。[结论]1.CVA4是2012年引起江苏赣榆县手足口病、病毒性脑炎以及疱疹性咽峡炎等疾病的主要病原体之一,在当地发生了较大规模的循环,并有多个病毒传播链。2.本研究首次基于CVA4毒株VP1区编码基因全长,将CVA4划分为5个基因型,分别为A、B、C、D、E基因型,基于VP1区3’端序列亲缘进化分析也进一步验证了基因型的划分。分离于中国大陆的所有CVA4病毒都属于E基因型中的E1和E2基因亚型。3.2009年1株广东省的EV71分离株在3D区可能与中国大陆现流行的CVA4发生了重组,应关注CVA4的3D区作为供体在肠道病毒重组的作用,同时关注EV71重组CVA4对EV71生物学性状和传播力和致病力的影响。4.本研结果为CVA4引起的HDMD等传染病的诊断、防控工作提供了重要的病毒学基础资料。
[Abstract]:[BACKGROUND] Human Enterovirus (HEV) belongs to the genus Enterovirus of the Picornavirdae family. At present, 119 serotypes have been reported and divided into four groups: EV-A, EV-B, EV-C and EV-D. In most cases, patients infected with HEV are asymptomatic or cause only mild symptoms, such as fever, rash, or EV-D. Mild upper respiratory symptoms; but sometimes HEV infection can also cause a wide range of clinical diseases, such as acute hemorrhagic conjunctivitis, aseptic meningitis, acute flaccid paralysis (AFP), hand, foot and mouth disease (Hand, Foot and Mouth Disease, myocarditis, cold-like diseases, etc. In recent years, caused by HEV a variety of diseases. The genome of the HEV virus is a single strand of positive strand RNA, about 7.5 KB long. The whole genome contains only one Open Reading Frame (ORF), encodes a polyprotein, and finally hydrolyzes to produce VP1-VP4 with four structural proteins and seven non-structural proteins. VP1 protein is the main structure that recognizes and binds to receptors on the host cells and contains important serotype-specific neutralizing sites; VP1 protein is located in the outermost appearance of viral particles and mutates under the immune pressure to form different epidemic strains. Hand-foot-mouth disease (HFMD) is a common infectious disease caused by a variety of enteroviruses (EV). Since the outbreak of HFMD in the mainland of China in 2007, hand-foot-mouth disease (HFMD) has gradually attracted attention, according to the relevant literature in recent years. It is reported that HFMD has become one of the major public health problems that seriously threaten the health and life safety of the broad population, especially children. EV71 and CA16 are the main pathogens causing HFMD. EV71 and CA16 are the main pathogens of HFMD. The etiological studies of HFMD are mostly focused on EV71 and CA16, and other intestines. However, in recent years, HFMD surveillance data in some areas show that the pathogenic composition of other enteroviruses has increased, and CVA4 is one of them. [Objective] Through systematic analysis of VP1 and 3D gene characteristics of CVA4 strains from HFMD cases in mainland China from 2008 to 2012, to elucidate their genetic variation in China and enrich the CVA4 strain library and gene information database in China and the world, so as to provide scientific support for the diagnosis, prevention and control of HFMD caused by CVA4 in China. Source of the virus: In 2012, 1246 HFMD, viral encephalitis and herpes angina were isolated from clinical specimens of Ganyu County, Jiangsu Province, 57 strains of CVA4 virus were isolated; in 2008-2012, 19 strains of CVA4.2 were isolated from HFMD cases in other areas by HFMD Surveillance Network Laboratory of mainland China. Gene sequencing: virus RNA was extracted, VP 1 and 3D region genes were amplified by RT-PCR. Bioinformatics analysis: The VP1 and 3D genes of CVA4 in this study were compared with the VP1 and 3D genes of CVA4 retrieved from GenBank in China and other countries and regions by using BioEdit Sequence Alignment Editor software 7.0. The phylogenetic tree of VP1 and 3D regions was constructed by Neighbor-joining method, and the phylogenetic relationship and evolution were analyzed. [Results] 1. HFMD, viral encephalitis, herpes angina and other clinical specimens in Ganyu County, Jiangsu Province were separated. Among 350 strains, CVB3 (142 strains), CVA4 (57 strains), CVA10 (31 strains), CVA16 (29 strains), EV71 (24 strains), etc. CVA4 ranked second, accounting for 16%. The 564 nucleotide sequence homology of 57 CVA4 strains isolated from Ganyu County was 94.0%-100%, amino acid sequence homology was 97.8%-100%. Two strains were selected as 915 nucleotides of VPl coding region gene. The nucleotide sequence homology and amino acid sequence homology were 94.1% - 100% and 97.3% - 100% respectively. The homology was high and the evolutionary relationship was close. 3. The VP1 sequences of 21 CVA4 representative strains from 2008 to 2012 obtained from China and isolated from GenBank were analyzed. The VP1 sequences of 10 CVA4 isolates from mainland China were analyzed for homology: 31 CVA4 isolates from mainland China had 85.5% - 100% homology in VP1 region, 97.5% - 100% homology in amino acid sequence and high homology, belonging to the same genotype. The nucleotide mutations were mostly synonymous mutations; two AFP isolates from Shandong Province in 1998. The nucleotide sequence homology of CVA4 strain was 88.5% - 89.9% compared with other isolates. Excluding the isolates from 1998, the homology of nucleotide sequence and amino acid sequence between other HFMD and AFP isolates was 94.8% and 98.4%, respectively. There was no specific difference between the two types of cases. The nucleotide sequence homology and amino acid sequence homology were 95.5%, 98.8% and 95.5%, respectively. There were no specific differences in nucleotides and amino acids between the two types of HFMD cases. 4. The VP1 sequences of 21 representative CVA4 strains obtained in this study and the VP1 sequences of 21 global CVA4 strains obtained in GenBank were used as phylogenetic trees. Based on the international enterovirus genotyping standard, CVA4 can be divided into five genotypes according to the full length of VP1 coding gene, namely A, B, C, D and E genotypes. This is the first genotyping of CVA4 based on the full length of VP1 gene. 31 strains of CVA4 virus isolated from mainland China belong to E genotype, and E genotype is divided into E1 and E2 genotype. E1 genotype includes 2 strains isolated from AFP cases in Shandong Province in 1998 and 1 strain isolated from AFP cases in Jilin Province in 2006. E2 genotype includes 22 strains of CVA4 isolated from HFMD cases in 2008-2012. The average genetic distance of nucleotide sequences between E1 and E2 genotypes was 12.6%. It was found that there were at least two large transmission chains in mainland China. E1 genotype was predominant in 2006 and before, and E2 genotype was predominant after 2006. The sequence information of VP1 region 3'end of CVA4 in ank was more abundant than that of VP1 region. Based on the VP1 region 3'end of 420 nucleotide sequences of 21 CVA4 strains in this study, 420 nucleotide sequences of VP1 region and 44 CVA4 VP1 region 3'end of representative strains in GenBank were used as phylogenetic trees. The genetic distances were 13.4%-26.1% and 5.8%-9.6% respectively among the nucleotide sequences of Lineage A-E. The evolutionary branches were consistent with the results of the evolutionary tree of VP1 gene length. The genotypes A-E contained 31 strains of CVA4 isolated from mainland China. Viruses belong to Lineage E. Lineage E can also be divided into Lineage E1 and Lineage E2, and the results are consistent with the VP1 full-length division. Lineage E includes not only the Chinese mainland strains, but also the Taiwan strains. 57 strains of CVA 4 isolated from Ganyu County, Jiangsu Province. Sequence analysis based on the 5'end indicates that all of them are E2 genotypes. 5 CVA4 representative strains were selected to complete the 3D region sequencing and compared with other retrievable CVA4, HEV-A group enterovirus prototypes, BLAST high homology strains and EV71 C4a genotype representative strains to construct phylogenetic tree: 5 CVA4 strains and 2009 isolation from China. The CVA 4 strain from Shenzhen (HQ728260) and EV71 strain (JF 799986) isolated from Guangdong Province in 2009 had a high homology of 94.6% - 96% in one evolutionary branch; the genetic distance between the prototype strain of EV71 and BrCr strain of EV71 or other representative strains of EV71 C4a genotype was relatively long, and the sequence homology was only 73.3% - 81.7%. CVA4 is one of the main pathogens causing hand-foot-mouth disease, viral encephalitis, herpes angina and other diseases in Ganyu County, Jiangsu Province in 2012. It has a large-scale circulation and multiple transmission chains. 2. This study is the first time to compile the VP1 region of CVA4 strain. All CVA4 viruses isolated from mainland China belong to E1 and E2 subtypes of E genotype. 3. A Guangdong EV71 strain isolated in 2009 may be associated with a 3 D region EV71 strain. The present epidemic CVA4 in China has been recombined. We should pay attention to the role of the 3D region of CVA4 as a donor in the recombination of enteroviruses. At the same time, we should pay attention to the effects of the recombinant CVA4 on the biological characteristics, transmission and pathogenicity of EV71. 4. The results of this study provide important virological basic data for the diagnosis and prevention of infectious diseases such as HDMD caused by CVA4.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R512.5
本文编号：2216104
[Abstract]:[BACKGROUND] Human Enterovirus (HEV) belongs to the genus Enterovirus of the Picornavirdae family. At present, 119 serotypes have been reported and divided into four groups: EV-A, EV-B, EV-C and EV-D. In most cases, patients infected with HEV are asymptomatic or cause only mild symptoms, such as fever, rash, or EV-D. Mild upper respiratory symptoms; but sometimes HEV infection can also cause a wide range of clinical diseases, such as acute hemorrhagic conjunctivitis, aseptic meningitis, acute flaccid paralysis (AFP), hand, foot and mouth disease (Hand, Foot and Mouth Disease, myocarditis, cold-like diseases, etc. In recent years, caused by HEV a variety of diseases. The genome of the HEV virus is a single strand of positive strand RNA, about 7.5 KB long. The whole genome contains only one Open Reading Frame (ORF), encodes a polyprotein, and finally hydrolyzes to produce VP1-VP4 with four structural proteins and seven non-structural proteins. VP1 protein is the main structure that recognizes and binds to receptors on the host cells and contains important serotype-specific neutralizing sites; VP1 protein is located in the outermost appearance of viral particles and mutates under the immune pressure to form different epidemic strains. Hand-foot-mouth disease (HFMD) is a common infectious disease caused by a variety of enteroviruses (EV). Since the outbreak of HFMD in the mainland of China in 2007, hand-foot-mouth disease (HFMD) has gradually attracted attention, according to the relevant literature in recent years. It is reported that HFMD has become one of the major public health problems that seriously threaten the health and life safety of the broad population, especially children. EV71 and CA16 are the main pathogens causing HFMD. EV71 and CA16 are the main pathogens of HFMD. The etiological studies of HFMD are mostly focused on EV71 and CA16, and other intestines. However, in recent years, HFMD surveillance data in some areas show that the pathogenic composition of other enteroviruses has increased, and CVA4 is one of them. [Objective] Through systematic analysis of VP1 and 3D gene characteristics of CVA4 strains from HFMD cases in mainland China from 2008 to 2012, to elucidate their genetic variation in China and enrich the CVA4 strain library and gene information database in China and the world, so as to provide scientific support for the diagnosis, prevention and control of HFMD caused by CVA4 in China. Source of the virus: In 2012, 1246 HFMD, viral encephalitis and herpes angina were isolated from clinical specimens of Ganyu County, Jiangsu Province, 57 strains of CVA4 virus were isolated; in 2008-2012, 19 strains of CVA4.2 were isolated from HFMD cases in other areas by HFMD Surveillance Network Laboratory of mainland China. Gene sequencing: virus RNA was extracted, VP 1 and 3D region genes were amplified by RT-PCR. Bioinformatics analysis: The VP1 and 3D genes of CVA4 in this study were compared with the VP1 and 3D genes of CVA4 retrieved from GenBank in China and other countries and regions by using BioEdit Sequence Alignment Editor software 7.0. The phylogenetic tree of VP1 and 3D regions was constructed by Neighbor-joining method, and the phylogenetic relationship and evolution were analyzed. [Results] 1. HFMD, viral encephalitis, herpes angina and other clinical specimens in Ganyu County, Jiangsu Province were separated. Among 350 strains, CVB3 (142 strains), CVA4 (57 strains), CVA10 (31 strains), CVA16 (29 strains), EV71 (24 strains), etc. CVA4 ranked second, accounting for 16%. The 564 nucleotide sequence homology of 57 CVA4 strains isolated from Ganyu County was 94.0%-100%, amino acid sequence homology was 97.8%-100%. Two strains were selected as 915 nucleotides of VPl coding region gene. The nucleotide sequence homology and amino acid sequence homology were 94.1% - 100% and 97.3% - 100% respectively. The homology was high and the evolutionary relationship was close. 3. The VP1 sequences of 21 CVA4 representative strains from 2008 to 2012 obtained from China and isolated from GenBank were analyzed. The VP1 sequences of 10 CVA4 isolates from mainland China were analyzed for homology: 31 CVA4 isolates from mainland China had 85.5% - 100% homology in VP1 region, 97.5% - 100% homology in amino acid sequence and high homology, belonging to the same genotype. The nucleotide mutations were mostly synonymous mutations; two AFP isolates from Shandong Province in 1998. The nucleotide sequence homology of CVA4 strain was 88.5% - 89.9% compared with other isolates. Excluding the isolates from 1998, the homology of nucleotide sequence and amino acid sequence between other HFMD and AFP isolates was 94.8% and 98.4%, respectively. There was no specific difference between the two types of cases. The nucleotide sequence homology and amino acid sequence homology were 95.5%, 98.8% and 95.5%, respectively. There were no specific differences in nucleotides and amino acids between the two types of HFMD cases. 4. The VP1 sequences of 21 representative CVA4 strains obtained in this study and the VP1 sequences of 21 global CVA4 strains obtained in GenBank were used as phylogenetic trees. Based on the international enterovirus genotyping standard, CVA4 can be divided into five genotypes according to the full length of VP1 coding gene, namely A, B, C, D and E genotypes. This is the first genotyping of CVA4 based on the full length of VP1 gene. 31 strains of CVA4 virus isolated from mainland China belong to E genotype, and E genotype is divided into E1 and E2 genotype. E1 genotype includes 2 strains isolated from AFP cases in Shandong Province in 1998 and 1 strain isolated from AFP cases in Jilin Province in 2006. E2 genotype includes 22 strains of CVA4 isolated from HFMD cases in 2008-2012. The average genetic distance of nucleotide sequences between E1 and E2 genotypes was 12.6%. It was found that there were at least two large transmission chains in mainland China. E1 genotype was predominant in 2006 and before, and E2 genotype was predominant after 2006. The sequence information of VP1 region 3'end of CVA4 in ank was more abundant than that of VP1 region. Based on the VP1 region 3'end of 420 nucleotide sequences of 21 CVA4 strains in this study, 420 nucleotide sequences of VP1 region and 44 CVA4 VP1 region 3'end of representative strains in GenBank were used as phylogenetic trees. The genetic distances were 13.4%-26.1% and 5.8%-9.6% respectively among the nucleotide sequences of Lineage A-E. The evolutionary branches were consistent with the results of the evolutionary tree of VP1 gene length. The genotypes A-E contained 31 strains of CVA4 isolated from mainland China. Viruses belong to Lineage E. Lineage E can also be divided into Lineage E1 and Lineage E2, and the results are consistent with the VP1 full-length division. Lineage E includes not only the Chinese mainland strains, but also the Taiwan strains. 57 strains of CVA 4 isolated from Ganyu County, Jiangsu Province. Sequence analysis based on the 5'end indicates that all of them are E2 genotypes. 5 CVA4 representative strains were selected to complete the 3D region sequencing and compared with other retrievable CVA4, HEV-A group enterovirus prototypes, BLAST high homology strains and EV71 C4a genotype representative strains to construct phylogenetic tree: 5 CVA4 strains and 2009 isolation from China. The CVA 4 strain from Shenzhen (HQ728260) and EV71 strain (JF 799986) isolated from Guangdong Province in 2009 had a high homology of 94.6% - 96% in one evolutionary branch; the genetic distance between the prototype strain of EV71 and BrCr strain of EV71 or other representative strains of EV71 C4a genotype was relatively long, and the sequence homology was only 73.3% - 81.7%. CVA4 is one of the main pathogens causing hand-foot-mouth disease, viral encephalitis, herpes angina and other diseases in Ganyu County, Jiangsu Province in 2012. It has a large-scale circulation and multiple transmission chains. 2. This study is the first time to compile the VP1 region of CVA4 strain. All CVA4 viruses isolated from mainland China belong to E1 and E2 subtypes of E genotype. 3. A Guangdong EV71 strain isolated in 2009 may be associated with a 3 D region EV71 strain. The present epidemic CVA4 in China has been recombined. We should pay attention to the role of the 3D region of CVA4 as a donor in the recombination of enteroviruses. At the same time, we should pay attention to the effects of the recombinant CVA4 on the biological characteristics, transmission and pathogenicity of EV71. 4. The results of this study provide important virological basic data for the diagnosis and prevention of infectious diseases such as HDMD caused by CVA4.
【学位授予单位】：中国疾病预防控制中心
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R512.5
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相关期刊论文 前8条
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