肠道病毒71型感染机制研究进展

重症手足口病及其死亡病例多由肠道病毒71型(Enterovirus A71,EV-A71)感染引起,且近年来在亚太地区广泛流行。由于EV-A71具有严格的宿主细胞寄生性,需依赖细胞的能量和代谢系统完成其复制过程。因此研究该病毒在进入、脱衣壳等感染早期过程中病毒与宿主相互作用的机制,不仅有助于理解其致病机理,同时可为建立相应预防和治疗的策略提供科学依据。为此,就EV-A71感染早期的致病机制的研究进展进行了综述。     

人肠道病毒71型动物模型研究进展

人肠道病毒71型是婴幼儿手足口病的致病原之一,其严重的并发症可导致神经系统疾病,甚至死亡,是近期威胁中国儿童健康的因素之一。目前尚无临床疫苗可以预防该病毒感染,而EV71的动物模型是进行致病机理、疫苗评价和药物等研究的基础。本文对EV71的两种常用动物模型：小鼠和猕猴（Macaca mulatta）模型进行了描述,并对其在研究中的应用给与概括,为研究者选择合适的动物模型提供了依据。     

肠道病毒71型研究进展

肠道病毒71型是一种具有较强致病性的肠道病毒,主要引起患者手足口病(Hand,foot and mouth disease,HFMD)。已在世界多个地区爆发和流行,主要症状是手、足、口、臀等部位皮疹或疱疹,少数患儿可以并发无菌性脑膜炎、脑炎、急性弛缓性麻痹等严重神经系统并发症,呼吸道感染和心肌炎等,可致残、致死。2007—2008年中国多个地区均有较大规模流行,危害十分严重。近四十年的多次流行中,EV71病毒的基因不断进化,研究其基因变化特点对早期诊断、分型以及了解基因与流行、致病的关系等有着重要的意义。对EV71感染尚缺乏有效的抗病毒药物,研制有效的预防性疫苗迫在眉睫,目前有灭活疫苗、减毒疫苗、多肽或蛋白疫苗、DNA疫苗等多种尝试,但至今尚无EV71疫苗上市。本文对EV71基因、实验室诊断和疫苗方面的研究进展进行了综述。     

肠道病毒71型疫苗质量控制研究进展

手足口病(Hand foot and mouth disease,HFMD)已成为西太平洋区严重的公共卫生问题之一,肠道病毒71型(Enterovirus 71,EV71)是引起HFMD的主要病原体,研发疫苗是控制HFMD流行的有效手段。目前世界范围已有5个EV71全病毒灭活疫苗进入临床试验,其中中国研制的3种EV71疫苗已分别完成III期临床试验,结果表明3种疫苗都具有良好的安全性和保护效果。在EV71疫苗研发中,抗原质控的方法和标准是研发的瓶颈,其中抗原活性测定是工序工艺优化、免疫原性评价和剂量确定的关键指标。综述了EV71疫苗抗原质控的研究进展。     

肠道病毒71型的研究进展

肠道病毒71型(enterovirus71,EV71)是小RNA病毒科(Picornaviridae)肠道病毒属(Enterovirus)成员,其感染主要引起患者手足口病(hand-foot-and-mouth disease,HFMD).通常情况下,EV71感染引起的HFMD在临床症状等方面与柯萨奇病毒A16(Coxsackie A16,CA16)引起的手足口病难以区别,但EV71感染除了引起HFMD以外,还能够引起无菌性脑膜炎(aseptic meningitis)、脑干脑炎(brainstem encephalitis)和脊髓灰质炎样的麻痹(poliomyelitis-like paralysis)等多种与神经系统相关的疾病[1].自1974年首次报道[2]以来,EV71已在世界范围内引起十多次爆发与流行[3-6].近年来,EV71病毒的流行在亚太地区呈上升趋势[7-9].根据病毒衣壳蛋白VP1核苷酸序列的差异,可将EV71分为A、B、C 3个基因型,其中,B型和C型又进一步分为B1、B2、B3、B4以及C1和C2亚型[10-12].     

抗肠道病毒71型的药物研究进展

肠道病毒71型（Enterovirus 71,EV71）是引起重症手足口病（Hand,Foot and Mouth Disease,HFMD）的主要病原体。重症HFMD进展迅速,可表现为严重的神经系统并发症,甚至危及生命。目前临床上防治EV71感染缺乏特异、高效的药物,其残疾率和死亡率很高。随着研究的深入,已经发现了大量具有抗EV71能力的化合物,人们探索的药物机制和药物靶点各不相同。因此,本文从药物靶向病毒、宿主等角度出发,针对抗EV71感染的天然药物、合成药物及常见中药中活性成分作用机制的最新进展进行综述与讨论。此外,对抗病毒药物筛选技术进行简要概述,以期为抗EV71药物的筛选与研发设计等相关研究提供参考。     

肠道病毒71型致神经源性肺水肿发病机制研究进展

肠道病毒71型(EV71)是人类肠道病毒的一种,近30年来,EV71感染在亚太地区广泛流行,是手足口病重症病例的主要病原体之一.EV71感染最严重的并发症为中枢神经系统和呼吸系统受累,其中神经源性肺水肿病程进展迅速、治疗困难、病死率高,近年来受到人们的广泛关注,但其发病机制目前尚不十分清楚.本研究对EV71感染导致的神经源性肺水肿的发病机制从脑干脑炎、全身炎症反应及免疫等方面的研究进展作一综述.     

肠道病毒71型感染患儿血中炎症因子mRNA的表达

目的探讨肠道病毒71型(EV71)感染患儿血中炎症因子mRNA的表达。方法用Real-time PCR方法检测EV71感染轻症、重症患儿和正常儿童的血中肿瘤坏死因子α(TNF-α),干扰素(IFN)-α、IFN-β,白细胞介素-6(IL-6)、IL-8、IL-12的mRNA表达。结果EV71感染患儿血中IFN-α、IL-6、IL-8、IL-12mRNA的表达增加(28±182.07 vs 5.5±0.79;30±103.30 vs 6±4.21;34±169.60 vs6.2±4.16;33.33±229.70 vs 2.6±0.92)。轻症组与重症组间比较,IFN-α、IL-12mRNA表达显著升高(40±275.86 vs 28±182.07;46.67±46.04 vs 33.33±229.7),IL-6、IL-8mRNA的表达差异无统计学意义(30±103.3 vs 32±110.5;34±169.6 vs 36.67±195.4)。结论细胞因子IFN-α、IL-6、IL-8、IL-12参与抗EV71感染过程,其中IFN-α和IL-12可能是促进EV71感染发展为重症的关键因子。     

肠道病毒71型分子流行病学研究进展

肠道病毒71型(Enterovirus type 71,EV71),自1974年首次报道以来,在世界范围内引起多次爆发与流行。EV71感染主要引起患者手足口病(hand,foot and mouth disease,HFMD),在临床上与柯萨奇病毒A16(Coxsakie A16,CA16)感染所引起的手足口病难以区别,但EV71还能够引起多种与神经系统相关的疾病。近年来,EV71病毒的流     

肠道病毒71型实验室诊断研究进展

肠道病毒71型(Enterovirus 71,EV71)为手足口病(Handf,oot and mouth disease,HFMD)和相关疾病的主要病原体,多感染婴幼儿,少数病例可以并发呼吸道感染和心肌炎、无菌性脑膜炎、脑炎、急性弛缓性麻痹等严重疾病,可致残、致死。因此EV71实验室诊断对EV71引起疾病的治疗和防控具有重要意义。本文将从核酸检测、抗体检测及其他检测等三部分对EV71的实验室诊断方法研究进展进行了综述。     

Hand foot and mouth disease due to enterovirus 71 in Malaysia

Hand foot and mouth disease is a febrile sickness complex characterized by cutaneous eruption (exanthem) on the palms and soles with simultaneous occurrence of muco-cutanous vesiculo-ulcerative lesions (enanthem) affecting the mouth.The illness is caused by a number of enteroviruses with coxsackievirus A16 and enterovirus 71 as the main causative agents.Human enterovirus 71 (EV71) belongs to the species Human enterovirus A under the genus Enterovirus within the family Picornaviridae.EV71 has been associated with an array of clinical diseases including hand foot and mouth disease (HFMD),aseptic meningitis,encephalitis and poliomyelitis-like acute flaccid paralysis.A large outbreak of HFMD due to highly neurovirulent EV71 emerged in Malaysia in 1997,and caused 41deaths amongst young children.In late 2000,a recurrence of an outbreak of HFMD occurred in Malaysia with S fatalities in peninsular Malaysia.Outbreak of HFMD due to EV71 recurred in 2003 with an unknown number of cases and mortalities.A similar outbreak of HFMD with 2 recorded deaths in young children occurred in peninsular Malaysia in late 2005 and this was followed by a larger outbreak in Sarawak (Malaysian Borneo) with 6 reported fatalities in the early part of 2006.The current on-going outbreak of HFMD started in peninsular Malaysia in epidemiological week 12 of 2010.As with other HFMD outbreaks in Malaysia,both EV71 and CA16 were the main aetiological viruses isolated.In similarity with the HFMD outbreak in 2005,the isolation of CA16 preceded the appearance of EV71.Based on the VP 1 gene nucleotide sequences,4 sub-genogroups of EV71 (C1,C2,B3 and B4) co-circulated and caused the outbreak of hand,foot and mouth disease in peninsular Malaysia in 1997.Two sub-genogroups (C1 and B4) were noted to cause the outbreak in 2000 in both peninsular Malaysia and Sarawak.EV71 of sub-genogroup B5 with smaller contribution from sub-genogroup C1 caused the outbreak in 2003.In the 2005 outbreak,besides the EV71 strains of sub-genogroup C1,EV71 strains belonging to sub-genogroup B5 were isolated but formed a cluster which was distinct from the EV71 strains from the sub-genogroup B5 isolated in 2003.The four EV71 strains isolated from clinical specimens of patients with hand,foot and mouth disease in the Sarawak outbreak in early 2006 also belonged to sub-genogroup B5.Phylogenetic analysis of the VP1 gene suggests that the EV71 strains causing the outbreak in Sarawak could have originated from peninsular Malaysia.Epidemiological and molecular data since 1997 show the recurrence of HFMD due to EV71 in Malaysia every 2 to 4 years.In each of the past outbreaks,more than one sub-genogroup of the virus co-circulate.     

Epidemiology and seroepidemiology of human enterovirus 71 among Thai populations

Background

Human enterovirus 71 (EV71) is an important pathogen caused large outbreaks in Asian-Pacific region with severe neurological complications and may lead to death in young children. Understanding of the etiological spectrum and epidemic changes of enterovirus and population’s immunity against EV71 are crucial for the implementation of future therapeutic and prophylactic intervention.

Results

A total of 1,182 patients who presented with the symptoms of hand foot and mouth disease (67.3%) or herpangina (HA) (16.7%) and admitted to the hospitals during 2008-2013 were tested for enterovirus using pan-enterovirus PCR targeting 5′-untranslated region and specific PCR for viral capsid protein 1 gene. Overall, 59.7% were pan-enterovirus positive comprising 9.1% EV71 and 31.2% coxsackievirus species A (CV-A) including 70.5% CV-A6, 27.6% CV-A16, 1.1% CV-A10, and 0.8% CV-A5. HFMD and HA occurred endemically during 2008-2011. The number of cases increased dramatically in June 2012 with the percentage of the recently emerged CV-A6 significantly rose to 28.4%. Co-circulation between different EV71 genotypes was observed during the outbreak. Total of 161 sera obtained from healthy individuals were tested for neutralizing antibodies (NAb) against EV71 subgenotype B5 (EV71-B5) using microneutralization assay. The seropositive rate of EV71-B5 was 65.8%. The age-adjusted seroprevalence for individuals was found to be lowest in children aged >6 months to 2 years (42.5%). The seropositive rate remained relatively low in preschool children aged > 2 years to 6 years (48.3%) and thereafter increased sharply to more than 80% in individuals aged > 6 years.

Conclusions

This study describes longitudinal data reflecting changing patterns of enterovirus prevalence over 6 years and demonstrates high seroprevalences of EV71-B5 NAb among Thai individuals. The rate of EV71 seropositive increased with age but without gender-specific significant difference. We identified that relative lower EV71 seropositive rate in early 2012 may demonstrate widely presented of EV71-B5 in the population before account for a large outbreak scale epidemic occurred in 2012 with due to a relatively high susceptibility of the younger population.     

Recent developments in antiviral agents against enterovirus 71 infection

Enterovirus 71 (EV-71) is the main etiological agent of hand, foot and mouth disease (HFMD). Recent EV-71 outbreaks in Asia-Pacific were not limited to mild HFMD, but were associated with severe neurological complications such as aseptic meningitis and brainstem encephalitis, which may lead to cardiopulmonary failure and death. The absence of licensed therapeutics for clinical use has intensified research into anti-EV-71 development. This review highlights the potential antiviral agents targeting EV-71 attachment, entry, uncoating, translation, polyprotein processing, virus-induced formation of membranous RNA replication complexes, and RNA-dependent RNA polymerase. The strategies for antiviral development include target-based synthetic compounds, anti-rhinovirus and poliovirus libraries screening, and natural compound libraries screening. Growing knowledge of the EV-71 life cycle will lead to successful development of antivirals. The continued effort to develop antiviral agents for treatment is crucial in the absence of a vaccine. The coupling of antivirals with an effective vaccine will accelerate eradication of the disease.     

Hand Foot and Mouth Disease Due to Enterovirus 71 in Malaysia

Hand foot and mouth disease is a febrile sickness complex characterized by cutaneous eruption (exanthem) on the palms and soles with simultaneous occurrence of muco-cutanous vesiculo-ulcerative lesions (enanthem) affecting the mouth. The illness is caused by a number of enteroviruses with coxsackievirus A16 and enterovirus 71 as the main causative agents. Human enterovirus 71 (EV71) belongs to the species Human enterovirus A under the genus Enterovirus within the family Picornaviridae. EV71 has been associa...     

肠道病毒71型疫苗的研究进展

近年来,手足口病(Hand foot mouth disease,HFMD)在中国多次爆发流行,严重威胁公众健康,尤其是5岁以下的婴幼儿。而肠道病毒71型(Enterovirus 71,EV71)是引起手足口病的主要病原体之一,由于目前还无针对该疾病有效的抗病毒药物,研制疫苗是控制EV71流行最为有效的措施。目前EV71疫苗及相关研究均取得重大突破,本文就近年来关于EV71疫苗研发、动物模型等的研究进展作一综述。     

肠道病毒71型和柯萨奇病毒A16型多重反转录聚合酶链反应的建立及初步应用

本文旨在建立一种快速、高效的方法检测肠道病毒71型（EV71）和柯萨奇病毒A16型(CA16)的方法,以用于儿童手足口病的病原学监测。通过设计肠道病毒通用引物和CA16与EV71的型特异性引物,建立不同引物浓度配比及两阶段退火温度以提高检测敏感性和特异性的多重反转录聚合酶链反应（RT-PCR）方法,并对首都儿科研究所附属儿童医院2010年3~10月收集的371例手足口病患儿共381份临床标本同时进行病毒分离和核酸检测。结果显示,本研究建立的多重RT-PCR方法对CA16和EV71的最低模板检测浓度分别为5.32 pg/ml和0.64 pg/ml,反应特异度为100%。应用该方法检测381份手足口病临床标本的总阳性率为78.4%,其中CA16与EV71的检测阳性率分别为32.6%和35.8%,二者检测阳性比为1:1.1。以病毒分离为标准,多重RT-PCR对CA16及EV71检测的准确率分别为95.2%和98.6%。因此,本研究新建立的多重RT-PCR方法准确、简便,适用于较大量样本的手足口病病原学监测。2010年引起北京地区儿童手足口病的主要病原为CA16和EV71。     

2009～2011年上海市手足口病流行病学和病原学特征

为分析2009～2011年上海地区手足口病流行病学特征和病原构成,从国家疾病监测信息报告管理系统获取上海市2009～2011年手足口病流行病学资料;采用实时荧光反转录聚合酶链反应（RT-PCR）对来自上海18个区（县）的6676例手足口病病例标本进行肠道病毒核酸检测,对其中257份标本进行病毒分离;对27份人肠道病毒71型（HEV71）毒株进行VPl基因序列全长测定和分析。结果显示,2009～2011年上海市18个区（县）均有手足口病病例报道,地区分布元显著差异;≤5岁的婴幼儿为疾病高发年龄段;4～11月为发病高峰期。HEV71和柯萨奇病毒A组16型（CAl6）为主要病原,不同地区病原构成有所不同。实时荧光RT—PCR对6676例病例标本进行核酸检测,其中肠道病毒通用核酸检测阳性率为69．61％,HEV71和CAl6阳性率分别为38．83％和21．26％。对257份HEV71核酸阳性标本进行病毒分离,获得毒株57株,分离阳性率为22．18％。对其中27株进行VPl基因全长测序,均属C4a基因亚型。