BACKGROUND Hand,foot,and mouth disease(HFMD)has become one of the most common infectious diseases in China.Before 2016,the primary causal serotypes were enterovirus A71(EV-A71)and coxsackievirus A16(CV-A16).Following ...BACKGROUND Hand,foot,and mouth disease(HFMD)has become one of the most common infectious diseases in China.Before 2016,the primary causal serotypes were enterovirus A71(EV-A71)and coxsackievirus A16(CV-A16).Following the introduction of EV-A71 vaccines in China since 2016,the situation could change.CV-A6 has recently replaced EV-A71 and CV-A16 in some areas of China.However,the epidemiological characteristics of central China remain unknown.AIM To investigate the clinical symptoms and pathogen spectrum of HFMD in Shiyan City,central China,in recent years.METHODS The epidemiological,clinical,and laboratory data from HFMD cases reported to the Shiyan Center for Disease Control and Prevention between January 2016 and December 2020 were analyzed.196 throat swab specimens were collected from hospitalized HFMD patients between January 2018 and December 2020.To detect and genotype enteroviruses,real-time reverse transcription-polymerase chain reaction and sequencing of the 5'-untranslated region were used.In Shiyan,168 laboratory-confirmed HFMD cases were studied using a logistic regression model to determine the effect of predominant enterovirus serotypes.Based on the logistic regression model,the least absolute shrinkage and selection operator model was used to analyze the correlation between CV-A6 infection and various clinical characteristics in HFMD patients in Shiyan.RESULTS From 2016 to 2020,35840 HFMD cases were reported in Shiyan.The number of cases decreased by 48.4%from 2016 to 2017.Approximately 1.58-fold increases were found in 2018 and 2019 when compared to the previous year,respectively.In 2020,a decrease of about 85.5%was reported when compared to 2019.The most common serotypes shifted from EV-A71 and CV-A16(about 60%-80%in 2016 and 2018)to others(more than 80.0%in 2017,2019,and 2020).EV-A71 lost its dominance in 2017 in Shiyan.Among 196 confirmed HFMD cases,85.7%tested positive for enterovirus,with CV-A6 being the most common serotype(121/168,72.0%).The positive rates for CV-A16 and CVA10 were 4.8%and 3.0%,respectively.There was no EV-A71 discovered.Infection with CV-A6 was linked to fever,myocardial damage,increased creatine kinase MB isoenzyme,and lactate dehydrogenase levels.CONCLUSION CV-A6 was the most common enterovirus serotype in Shiyan City,replacing EV-A71 and CV-A16 as the HFMD pathogen.Developing vaccines against CV-A6 or multiple pathogens,as well as rising CV-A6 surveillance,will help prevent HFMD in central China.展开更多
This study bioinformatically analyzed the non-VP1 capsid proteins（VP2-VP4） of Coxasckievirus A6（CVA6）, with an attempt to predict their basic physicochemical properties, structural/functional features and linear B...This study bioinformatically analyzed the non-VP1 capsid proteins（VP2-VP4） of Coxasckievirus A6（CVA6）, with an attempt to predict their basic physicochemical properties, structural/functional features and linear B cell eiptopes. The online tools Sub Loc, Target P and the others from Ex PASy Bioinformatics Resource Portal, and SWISS-MODEL（an online protein structure modeling server）, were utilized to analyze the amino acid（AA） sequences of VP2-VP4 proteins of CVA6. Our results showed that the VP proteins of CVA6 were all of hydrophilic nature, contained phosphorylation and glycosylation sites and harbored no signal peptide sequences and acetylation sites. Except VP3, the other proteins did not have transmembrane helix structure and nuclear localization signal sequences. Random coils were the major conformation of the secondary structure of the capsid proteins. Analysis of the linear B cell epitopes by employing Bepipred showed that the average antigenic indices（AI） of individual VP proteins were all greater than 0 and the average AI of VP4 was substantially higher than that of VP2 and VP3. The VP proteins all contained a number of potential B cell epitopes and some eiptopes were located at the internal side of the viral capsid or were buried. We successfully predicted the fundamental physicochemical properties, structural/functional features and the linear B cell eiptopes and found that different VP proteins share some common features and each has its unique attributes. These findings will help us understand the pathogenicity of CVA6 and develop related vaccines and immunodiagnostic reagents.展开更多
Enteroviruses (EVs) are members of the genus Enteroviruswithin the orderPicornavirales, family Picornaviridae, and consist of 12 species, including EV-A, EV-B, EV-C, and EV-D, which are associated with human infection...Enteroviruses (EVs) are members of the genus Enteroviruswithin the orderPicornavirales, family Picornaviridae, and consist of 12 species, including EV-A, EV-B, EV-C, and EV-D, which are associated with human infections. Coxsackievirus B6 (CV-B6)belongs to the species EV-B, which currently consists of 63 serotypes, including echovirus (serotypes 1–7,9, 11–21, 24–27, 29–33), coxsackievirus group A (CVA9), coxsackievirus group B (CV-B, serotypes 1–6),the newly identified EVs (serotypes EV-B69, B73–75,B77–88, B93, B97–98, B100–101, B106–107, and B110–113), and the simian enterovirus SA5.展开更多
Coxsackievirus A6 of the D3a genotype(CVA6 D3a)is a primary pathogen causingmainland of China's hand,foot,and mouth disease(HFMD).Viral‐like particle(VLP)vaccines represent a potential candidate vaccine to preven...Coxsackievirus A6 of the D3a genotype(CVA6 D3a)is a primary pathogen causingmainland of China's hand,foot,and mouth disease(HFMD).Viral‐like particle(VLP)vaccines represent a potential candidate vaccine to prevent HFMD.This study collected Anti‐CVA6 D3a VLPs serum from BALB/c female mice immunized using CVA6 D3a VLPs.The neutralizing antibody levels were compared against the representative 14‐JX2018(D3a)and N4‐YN2015(D3b)strains between the antisera of different immune pathways.The immunoprotective effect of anti‐CVA6 D3a VLPs against these strains was monitored using pathological sections and immuno-histochemical results of lung and skeletal muscle tissues in seven‐day‐old Institute of Cancer Research(ICR)mice.Immunological protection against different branches of viruses was evaluated in 7‐day‐old(serum passive immune protection)and 14‐day‐old(VLPs active immune protection)neonatal ICR mice models.Serum‐neutralizing antibody levels were positively correlated with the number of immunizations and higher against 14‐JX2018 than against N4‐YN2015.Furthermore,these levels were significantly higher with abdominal injection than intramuscular injection.The immunized serum of 7‐day‐old ICR mice inoculated three times was 100%protected against CVA6 D3a 14‐JX2018(lethal titer:106.25 TCID 50)and CVA6 D3b N4‐YN2015(lethal titer:105.25TCID 50)fatal attacks,respectively.For ICR mice that have completed two active immunizations for 14 days,both CVA6 D3a 14‐JX2015(challenge titer:108.25 TCID 50)and CVA6 D3b N4‐YN2015(challenge titer:107.25 TCID 50)were used for the challenge,and the mice were able to survive.Overall,the CVA6 D3a VLPs prepared in this study are a potential vaccine candidate for CVA6,as it has the optimal protective effect against both CVA6 D3a and D3b evolutionary branches viruses.展开更多
Hand,foot,and mouth disease(HFMD)is one of the most common class C infectious diseases,posing a seri-ous threat to public health worldwide.Enterovirus A71(EV-A71)and coxsackievirus A16(CV-A16)have been regarded as the...Hand,foot,and mouth disease(HFMD)is one of the most common class C infectious diseases,posing a seri-ous threat to public health worldwide.Enterovirus A71(EV-A71)and coxsackievirus A16(CV-A16)have been regarded as the major pathogenic agents of HFMD;however,since an outbreak caused by coxsackievirus A6(CV-A6)in France in 2008,CV-A6 has gradually become the predominant pathogen in many regions.CV-A6 infects not only children but also adults,and causes atypical clinical symptoms such as a more generalized rash,eczema herpeticum,high fever,and onychomadesis,which are different from the symptoms associated with EV-A71 and CV-A16.Importantly,the rate of genetic recombination of CV-A6 is high,which can lead to changes in virulence and the rapid evolution of other characteristics,thus posing a serious threat to public health.To date,no specific vaccines or therapeutics have been approved for CV-A6 prevention or treatment,hence it is essential to fully understand the relationship between recombination and evolution of this virus.Here,we systematically review the genetic recombination events of CV-A6 that have occurred worldwide and explore how these events have promoted virus evolution,thus providing important information regarding future HFMD surveillance and prevention.展开更多
研究2013-2015年宁夏地区普通手足口病（hand,foot and mouth disease,HFMD）病例中柯萨奇病毒A组6型（Coxsackievirus A6,CV-A6）分离株基因特征。将2013-2015年收集的普通HFMD病例标本中所有非肠道病毒A71型（enterovirus,71）和非柯...研究2013-2015年宁夏地区普通手足口病（hand,foot and mouth disease,HFMD）病例中柯萨奇病毒A组6型（Coxsackievirus A6,CV-A6）分离株基因特征。将2013-2015年收集的普通HFMD病例标本中所有非肠道病毒A71型（enterovirus,71）和非柯萨奇病毒16型（Coxsackievirus A16,CV-A16）的其它肠道病毒（Enterovirus,EV）核酸阳性标本,使用RD细胞进行病毒分离,获得的毒株使用兼并引物进行VP1区基因扩增和测序,测序结果编辑后通过BLAST比对进行型别鉴定,选择CV-A6毒株进行基因进化分析。2013-2015年共收集非EV71和非CV-A16的EV阳性标本998份,共分离到227株毒株,其中61株鉴定为CV-A6,同源性分析表明宁夏61株CVA6间核苷酸和氨基酸序列同源性分别是96.1%-99.8%和98%-100%,与Gudla原型株同源性为82%-83.5%和93.8%-95.7%,遗传距离较远。CV-A6成为宁夏地区2013年和2015年其它肠道病毒中导致HFMD的主要病原体与国内流行的CV-A6具有较高的同源性,流行趋势一致,并且在宁夏地区存在多个传播链。展开更多
目的分析江苏省2012-2013年流行的柯萨奇病毒A组6型(coxsackievirus A6,CV-A6)毒株VP1区序列特征。方法采集江苏省2012-2013年10例CV-A6感染引发的手足口病(hand,foot and mouth disease,HFMD)患儿的咽拭子或肛拭子样本,通过RT-PCR扩增...目的分析江苏省2012-2013年流行的柯萨奇病毒A组6型(coxsackievirus A6,CV-A6)毒株VP1区序列特征。方法采集江苏省2012-2013年10例CV-A6感染引发的手足口病(hand,foot and mouth disease,HFMD)患儿的咽拭子或肛拭子样本,通过RT-PCR扩增完整VP1区。应用DNAStar软件包的MegAlign对CV-A6毒株的VP1区进行核苷酸和氨基酸序列比对分析,构建系统进化树。结果同源性和系统进化分析结果显示,10株流行株与2008年芬兰流行株同属于分支F,核苷酸同源性为95.1%~96.5%,而与原型株Gdula核苷酸同源性较低,为82.4%~84.0%。01-PZ/JS/2012、02-PZ/JS/2012、03-PZ/JS/2012、04-BY/JS/2012和08-PZ/JS/2013属于分支F2,05-PZ/JS/2013、06-PZ/JS/2013、07-PZ/JS/2013、09-PZ/JS/2013和10-BY/JS/2013属于F3,不同亚分支毒株之间核苷酸同源性为95.8%~97.2%。结论江苏省2012-2103年流行的10株毒株分别属于F2和F3分支,属于F2的5株毒株的VP1第30位氨基酸位点为V,而属于F3的5株毒株该位点为A。开展CV-A6流行株分子流行病学研究,了解毒株进化变异的趋势,对防控CV-A6引发的HFMD具有重要意义。展开更多
基金Supported by the Hubei Province Health and Family Planning A Scientific Research Project,No.WJ2017M220the Wuhan Health Bureau Scientific Research Fund,No.WX19C11+2 种基金the Joint Precision Medical Research Fund From Taihe Hospital,No.2016JZ10the Shiyan COVID-19 Pilot Emergency Scientific Research Project,No.20Y19the Wuhan Children's Hospital Research Project,No.2017FE007.
文摘BACKGROUND Hand,foot,and mouth disease(HFMD)has become one of the most common infectious diseases in China.Before 2016,the primary causal serotypes were enterovirus A71(EV-A71)and coxsackievirus A16(CV-A16).Following the introduction of EV-A71 vaccines in China since 2016,the situation could change.CV-A6 has recently replaced EV-A71 and CV-A16 in some areas of China.However,the epidemiological characteristics of central China remain unknown.AIM To investigate the clinical symptoms and pathogen spectrum of HFMD in Shiyan City,central China,in recent years.METHODS The epidemiological,clinical,and laboratory data from HFMD cases reported to the Shiyan Center for Disease Control and Prevention between January 2016 and December 2020 were analyzed.196 throat swab specimens were collected from hospitalized HFMD patients between January 2018 and December 2020.To detect and genotype enteroviruses,real-time reverse transcription-polymerase chain reaction and sequencing of the 5'-untranslated region were used.In Shiyan,168 laboratory-confirmed HFMD cases were studied using a logistic regression model to determine the effect of predominant enterovirus serotypes.Based on the logistic regression model,the least absolute shrinkage and selection operator model was used to analyze the correlation between CV-A6 infection and various clinical characteristics in HFMD patients in Shiyan.RESULTS From 2016 to 2020,35840 HFMD cases were reported in Shiyan.The number of cases decreased by 48.4%from 2016 to 2017.Approximately 1.58-fold increases were found in 2018 and 2019 when compared to the previous year,respectively.In 2020,a decrease of about 85.5%was reported when compared to 2019.The most common serotypes shifted from EV-A71 and CV-A16(about 60%-80%in 2016 and 2018)to others(more than 80.0%in 2017,2019,and 2020).EV-A71 lost its dominance in 2017 in Shiyan.Among 196 confirmed HFMD cases,85.7%tested positive for enterovirus,with CV-A6 being the most common serotype(121/168,72.0%).The positive rates for CV-A16 and CVA10 were 4.8%and 3.0%,respectively.There was no EV-A71 discovered.Infection with CV-A6 was linked to fever,myocardial damage,increased creatine kinase MB isoenzyme,and lactate dehydrogenase levels.CONCLUSION CV-A6 was the most common enterovirus serotype in Shiyan City,replacing EV-A71 and CV-A16 as the HFMD pathogen.Developing vaccines against CV-A6 or multiple pathogens,as well as rising CV-A6 surveillance,will help prevent HFMD in central China.
基金supported by the National Natural Science Foundation of China(No.81460304)Guangxi Natural Science Foundation(No.2015GXNSFDA139020)a research program sponsored by the Health Bureau of Guangxi Zhuang Autonomous Region,China(No.Z2014298)
文摘This study bioinformatically analyzed the non-VP1 capsid proteins（VP2-VP4） of Coxasckievirus A6（CVA6）, with an attempt to predict their basic physicochemical properties, structural/functional features and linear B cell eiptopes. The online tools Sub Loc, Target P and the others from Ex PASy Bioinformatics Resource Portal, and SWISS-MODEL（an online protein structure modeling server）, were utilized to analyze the amino acid（AA） sequences of VP2-VP4 proteins of CVA6. Our results showed that the VP proteins of CVA6 were all of hydrophilic nature, contained phosphorylation and glycosylation sites and harbored no signal peptide sequences and acetylation sites. Except VP3, the other proteins did not have transmembrane helix structure and nuclear localization signal sequences. Random coils were the major conformation of the secondary structure of the capsid proteins. Analysis of the linear B cell epitopes by employing Bepipred showed that the average antigenic indices（AI） of individual VP proteins were all greater than 0 and the average AI of VP4 was substantially higher than that of VP2 and VP3. The VP proteins all contained a number of potential B cell epitopes and some eiptopes were located at the internal side of the viral capsid or were buried. We successfully predicted the fundamental physicochemical properties, structural/functional features and the linear B cell eiptopes and found that different VP proteins share some common features and each has its unique attributes. These findings will help us understand the pathogenicity of CVA6 and develop related vaccines and immunodiagnostic reagents.
基金supported by the National Key Science and Technology Projects of China [Project Nos.2017ZX10104001,2018ZX10711001,and 2018ZX10713002]
文摘Enteroviruses (EVs) are members of the genus Enteroviruswithin the orderPicornavirales, family Picornaviridae, and consist of 12 species, including EV-A, EV-B, EV-C, and EV-D, which are associated with human infections. Coxsackievirus B6 (CV-B6)belongs to the species EV-B, which currently consists of 63 serotypes, including echovirus (serotypes 1–7,9, 11–21, 24–27, 29–33), coxsackievirus group A (CVA9), coxsackievirus group B (CV-B, serotypes 1–6),the newly identified EVs (serotypes EV-B69, B73–75,B77–88, B93, B97–98, B100–101, B106–107, and B110–113), and the simian enterovirus SA5.
基金supported by the National Key Researchand Development Programof China (Project No.2021YFC2302003).
文摘Coxsackievirus A6 of the D3a genotype(CVA6 D3a)is a primary pathogen causingmainland of China's hand,foot,and mouth disease(HFMD).Viral‐like particle(VLP)vaccines represent a potential candidate vaccine to prevent HFMD.This study collected Anti‐CVA6 D3a VLPs serum from BALB/c female mice immunized using CVA6 D3a VLPs.The neutralizing antibody levels were compared against the representative 14‐JX2018(D3a)and N4‐YN2015(D3b)strains between the antisera of different immune pathways.The immunoprotective effect of anti‐CVA6 D3a VLPs against these strains was monitored using pathological sections and immuno-histochemical results of lung and skeletal muscle tissues in seven‐day‐old Institute of Cancer Research(ICR)mice.Immunological protection against different branches of viruses was evaluated in 7‐day‐old(serum passive immune protection)and 14‐day‐old(VLPs active immune protection)neonatal ICR mice models.Serum‐neutralizing antibody levels were positively correlated with the number of immunizations and higher against 14‐JX2018 than against N4‐YN2015.Furthermore,these levels were significantly higher with abdominal injection than intramuscular injection.The immunized serum of 7‐day‐old ICR mice inoculated three times was 100%protected against CVA6 D3a 14‐JX2018(lethal titer:106.25 TCID 50)and CVA6 D3b N4‐YN2015(lethal titer:105.25TCID 50)fatal attacks,respectively.For ICR mice that have completed two active immunizations for 14 days,both CVA6 D3a 14‐JX2015(challenge titer:108.25 TCID 50)and CVA6 D3b N4‐YN2015(challenge titer:107.25 TCID 50)were used for the challenge,and the mice were able to survive.Overall,the CVA6 D3a VLPs prepared in this study are a potential vaccine candidate for CVA6,as it has the optimal protective effect against both CVA6 D3a and D3b evolutionary branches viruses.
文摘Hand,foot,and mouth disease(HFMD)is one of the most common class C infectious diseases,posing a seri-ous threat to public health worldwide.Enterovirus A71(EV-A71)and coxsackievirus A16(CV-A16)have been regarded as the major pathogenic agents of HFMD;however,since an outbreak caused by coxsackievirus A6(CV-A6)in France in 2008,CV-A6 has gradually become the predominant pathogen in many regions.CV-A6 infects not only children but also adults,and causes atypical clinical symptoms such as a more generalized rash,eczema herpeticum,high fever,and onychomadesis,which are different from the symptoms associated with EV-A71 and CV-A16.Importantly,the rate of genetic recombination of CV-A6 is high,which can lead to changes in virulence and the rapid evolution of other characteristics,thus posing a serious threat to public health.To date,no specific vaccines or therapeutics have been approved for CV-A6 prevention or treatment,hence it is essential to fully understand the relationship between recombination and evolution of this virus.Here,we systematically review the genetic recombination events of CV-A6 that have occurred worldwide and explore how these events have promoted virus evolution,thus providing important information regarding future HFMD surveillance and prevention.
文摘目的分析江苏省2012-2013年流行的柯萨奇病毒A组6型(coxsackievirus A6,CV-A6)毒株VP1区序列特征。方法采集江苏省2012-2013年10例CV-A6感染引发的手足口病(hand,foot and mouth disease,HFMD)患儿的咽拭子或肛拭子样本,通过RT-PCR扩增完整VP1区。应用DNAStar软件包的MegAlign对CV-A6毒株的VP1区进行核苷酸和氨基酸序列比对分析,构建系统进化树。结果同源性和系统进化分析结果显示,10株流行株与2008年芬兰流行株同属于分支F,核苷酸同源性为95.1%~96.5%,而与原型株Gdula核苷酸同源性较低,为82.4%~84.0%。01-PZ/JS/2012、02-PZ/JS/2012、03-PZ/JS/2012、04-BY/JS/2012和08-PZ/JS/2013属于分支F2,05-PZ/JS/2013、06-PZ/JS/2013、07-PZ/JS/2013、09-PZ/JS/2013和10-BY/JS/2013属于F3,不同亚分支毒株之间核苷酸同源性为95.8%~97.2%。结论江苏省2012-2103年流行的10株毒株分别属于F2和F3分支,属于F2的5株毒株的VP1第30位氨基酸位点为V,而属于F3的5株毒株该位点为A。开展CV-A6流行株分子流行病学研究,了解毒株进化变异的趋势,对防控CV-A6引发的HFMD具有重要意义。
