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the variations of vp1 protein might be associated with nervous system symptoms caused by enterovirus 71 infection.the vp1 protein of enterovirus 71 (ev71) is an important immunodominant protein which is responsible for host-receptor binding. nevertheless, the relationship between vp1 and neurovirulence is still poorly understood. in this study, we investigated the relationship between mutation of vp1 and neurovirulent phenotype of ev71 infection.201424886383
oral immunization with recombinant enterovirus 71 vp1 formulated with chitosan protects mice against lethal challenge.enterovirus 71 (ev71) is the etiologic agent of hand-foot-and-mouth disease (hfmd) in the asia-pacific region, many strategies have been applied to develop ev71 vaccines but no vaccines are currently available. mucosal immunization of the vp1, a major immunogenic capsid protein of ev71, may be an alternative way to prevent ev71 infection.201424885121
recombinant tandem multi-linear neutralizing epitopes of human enterovirus 71 elicited protective immunity in mice.human enterovirus 71 (ev71) has emerged as the leading cause of viral encephalitis in children, especially in the asia-pacific regions. ev71 vaccine development is of high priority at present, and neutralization antibodies have been documented to play critical roles during in vitro and in vivo protection against ev71 infection.201424885030
concentration and purification of enterovirus 71 using a weak anion-exchange monolithic column.enterovirus 71 (ev-71) is a neurotropic virus causing hand, foot and mouth disease (hfmd) in infants and children under the age of five. it is a major concern for public health issues across asia-pacific region. the most effective way to control the disease caused by ev-71 is by vaccination thus a novel vaccine is urgently needed. inactivated ev-71 induces a strong, virus-neutralizing antibody response in animal models, protecting them against a lethal ev-71 challenge and it has been shown to el ...201424884895
a novel universal neutralizing monoclonal antibody against enterovirus 71 that targets the highly conserved "knob" region of vp3 protein.hand, foot and mouth disease caused by enterovirus 71(ev71) leads to the majority of neurological complications and death in young children. while putative inactivated vaccines are only now undergoing clinical trials, no specific treatment options exist yet. ideally, ev71 specific intravenous immunoglobulins could be developed for targeted treatment of severe cases. to date, only a single universally neutralizing monoclonal antibody against a conserved linear epitope of vp1 has been identified. ...201424875055
a convenient nucleic acid test on the basis of the capillary convective pcr for the on-site detection of enterovirus 71.the recent and continuing epidemic of enterovirus 71 in china has affected millions of children and resulted in thousands of deaths. timely diagnosis and management is essential for disease control. current enterovirus 71 molecular tests require resources that are unavailable for on-site testing. we have developed a simple-to-operate nucleic acid test, the convenient and integrated nucleic acid test, for local medical institutions. it uses a convective pcr for rapid amplification, a dipstick for ...201424858492
complete genome sequence of a human enterovirus 71 strain isolated from a fatal case in shanghai, china, in 2012.the complete genome sequence of a human enterovirus 71 strain (sh12-276), isolated from a fatal case in shanghai in 2012, was determined. phylogenetic analysis based on the complete genome sequence classified this strain into subgenotype c4.201424855303
antiviral effects of two ganoderma lucidum triterpenoids against enterovirus 71 infection.enterovirus 71 (ev71) is a major causative agent for hand, foot and mouth disease (hfmd), and fatal neurological and systemic complications in children. however, there is currently no clinical approved antiviral drug available for the prevention and treatment of the viral infection. here, we evaluated the antiviral activities of two ganoderma lucidum triterpenoids (glts), lanosta-7,9(11),24-trien-3-one,15;26-dihydroxy (glta) and ganoderic acid y (gltb), against ev71 infection. the results showed ...201424845570
histopathological features and distribution of ev71 antigens and scarb2 in human fatal cases and a mouse model of enterovirus 71 infection.enterovirus 71 (ev71) is a neurotropic pathogen that causes hand, foot, and mouth disease. while infection is usually self-limiting, a minority of patients infected with ev71 develop severe neurological complications. in humans, ev71 has been reported to utilize the scavenger receptor class b, member 2 (scarb2) as a receptor for infectious cellular entry. in this study, we define the pathological features of ev71-associated disease as well as the distribution of ev71 antigen and scarb2 in human ...201424842162
risk factors of severe hand, foot and mouth disease: a meta-analysis.in recent years, outbreaks of hand, foot and mouth disease (hfmd) have increased, and more and more severe cases have appeared. we conducted a meta-analysis to generate large-scale evidence on the risk factors of severe hfmd.201424832848
seroepidemiology and molecular epidemiology of enterovirus 71 in russia.enterovirus 71 (ev71) is an emerging human pathogen causing massive epidemics of hand, foot and mouth disease with severe neurological complications in asia. ev71 also circulates in europe, however it does not cause large outbreaks. the reason for distinct epidemiological patterns of ev71 infection in europe and asia and the risk of ev71 epidemic in europe and russia remain unknown. seroepidemiology of ev71 and molecular epidemiology of occasional ev71 isolates were studied to explore circulatio ...201424819617
performance of reversed transcription loop-mediated isothermal amplification technique detecting ev71: a systematic review with meta-analysis.human enterovirus 71 (ev71) is the major etiological agent of hand, foot and mouth disease (hfmd), which is a common infectious disease in young children. studies in the past have shown that reversed transcription loop-mediated isothermal amplification (rt-lamp) was a rapid approach for the detection of ev71 in hfmd. this meta-analysis study is to evaluate the diagnostic role of rt-lamp in detecting ev71 infection. a comprehensive literature research of pubmed, embase, wan fang data, and chinese ...201424815384
association of viral replication capacity with the pathogenicity of enterovirus 71.enterovirus 71 (ev71) is a major cause of hand-foot-and-mouth disease, which is associated with fatal neurological disease. the mechanism of ev71 pathogenesis remains obscure. we compared the replication capacity of the severe and mild enterovirus 71 isolates. the replication kinetics of ev71 in rd cells and icr mice was determined by qrt-pcr. the lung, muscular, brain, intestine tissues were used for histopathological and immunohistochemical assays. the growth curves of ev71 strains in rd cells ...201424792876
enterovirus 71 virus propagation and purification.since its discovery in 1969, enterovirus 71 (ev71) has emerged as a serious worldwide health threat. this member of the picornavirus family causes hand, foot, and mouth disease, and also has the capacity to invade the central nervous system to cause severe disease and death. this is the propagation and purification procedure to produce infectious virion.201427547789
genetic polymorphism of ccl2-2510 and susceptibility to enterovirus 71 encephalitis in a chinese population.the study was performed in 36 chinese patients with enterovirus 71 (ev71) encephalitis and 141 patients with ev71-related hand, foot and mouth disease (hfmd) without encephalitis. genotyping was done by the polymerase chain reaction-restriction fragment length polymorphism technique. patients with ev71 encephalitis had a significantly higher frequency of the ccl2-2510gg genotypes when compared to patients with ev71-related hfmd without encephalitis (66.7% vs. 41.8%, p=0.028). the frequency of cc ...201424788844
mutations in the non-structural protein region contribute to intra-genotypic evolution of enterovirus 71.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 ev ...201424766641
in vitro and in vivo protection against enterovirus 71 by an antisense phosphorothioate oligonucleotide.enterovirus 71 (ev71) is a highly infectious virus that is a major cause of hand, foot, and mouth disease (hfmd), which can lead to severe neurological complications. currently, there is no effective therapy against ev71. five antisense oligodeoxynucleotides targeting the 5'-terminal conserved domain of the viral genome were designed using a method based on multiple predicted target mrna structures. they were then screened for anti-ev71 activity in vitro based on their ability to inhibit an ev71 ...201424756344
[histopathological changes in ev71-infected mouse model:a transmission electron microscopic study].to document ultrastructural changes of brain, spinal cord, skeletal muscle, jejunum and lung of ev71 infection mouse model, and to explore the myotropism and pathogenesis of ev71 in nervous system.201424742571
animal models of enterovirus 71 infection: applications and limitations.human enterovirus 71 (ev71) has emerged as a neuroinvasive virus that is responsible for several outbreaks in the asia-pacific region over the past 15 years. appropriate animal models are needed to understand ev71 neuropathogenesis better and to facilitate the development of effective vaccines and drugs. non-human primate models have been used to characterize and evaluate the neurovirulence of ev71 after the early outbreaks in late 1990s. however, these models were not suitable for assessing the ...201424742252
severe enterovirus type 71 nervous system infections in children in the shanghai region of china: clinical manifestations and implications for prevention and care.severe outbreaks of enterovirus 71 (ev71) have been on the rise in the western pacific region, including in china since 2007. we describe features of pediatric patients admitted with severe disease ev71 to a tertiary care hospital during the 2010 ongoing outbreak in the shanghai region.201424732390
update on enterovirus 71 infection.human enterovirus type 71 (ev71) has emerged as a major cause of viral encephalitis in children worldwide. the identified ev71 receptors provide useful information for understanding ev71replication and tissue tropism. host factors interact with the internal ribosome entry site (ires) of ev71 to regulate viral translation. however, the specific molecular features of the ev71 genome that determine virulence remain unclear. the ev71 capsid protein vp1 region might contribute to virulence and neurot ...201424727707
estimation of contamination sources of human enteroviruses in a wastewater treatment and reclamation system by pcr-dgge.a polymerase chain reaction-denaturing gradient gel electrophoresis (pcr-dgge) method was employed to estimate the contamination sources of human enteroviruses and understand how their dominant strains vary in a wastewater treatment and reclamation system consisting of sewage collection, wastewater treatment with membrane bioreactor and open lakes for reclaimed water storage and reuse. after pcr-dgge using a selected primer set targeting enteroviruses, phylogenetic analysis of acquired enterovir ...201424715657
detection of enterovirus 71 gene from clinical specimens by reverse-transcription loop-mediated isothermal amplification.the objective of this study was to develop a sensitive, specific and rapid approach to diagnose hand foot and mouth disease (hfmd) for an early treatment by using loop-mediated isothermal amplification (lamp) technique.201424713896
[the exploration of the role of angiopoietin-2 in pulmonary edema induced by ev71 infection].to observe the clinic character of pulmonary edema (pe) induced by enterovirus 71 (ev71) and the change in angiopoietin-2 (ang-2), and to explore the correlation between ang-2 and pe.201424696919
[an investigation on a case of hand-foot-mouth disease caused by coxsackie-virus a6 associated with a vaccine-derived poliovirus co-infection].to identify the pathogen and characteristics on a case of hand-foot-mouth disease (hfmd) caused by coxsackie-virus a6 (ca6) associated with vaccine-derived poliovirus (vdpv) co-infection.201424685040
the multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating ires-dependent translation of viral proteins.the activation of erk and p38 signal cascade in host cells has been demonstrated to be essential for picornavirus enterovirus 71 (ev71) replication and up-regulation of virus-induced cyclooxygenase-2 (cox-2)/prostaglandins e2 (pge2) expression. the aim of this study was to examine the effects of sorafenib, a clinically approved anti-cancer multi-targeted kinase inhibitor, on the propagation and pathogenesis of ev71, with a view to its possible mechanism and potential use in the design of therapy ...201424680956
prenylated benzoylphloroglucinols and xanthones from the leaves of garcinia oblongifolia with antienteroviral activity.an acetone extract of the leaves of garcinia oblongifolia showed antiviral activity against enterovirus 71 (ev71) using a cytopathic effect inhibition assay. bioassay-guided fractionation yielded 12 new prenylated benzoylphloroglucinols, oblongifolins j-u (1-12), and five known compounds. the structures of 1-12 were elucidated by spectroscopic analysis including 1d- and 2d-nmr and mass spectrometry methods. the absolute configurations were determined by a combination of a mosher ester procedure ...201424679044
phenotypic and genotypic characteristics of novel mouse cell line (nih/3t3)-adapted human enterovirus 71 strains (ev71:tllm and ev71:tllmv).since its identification in 1969, enterovirus 71 (ev71) has been causing periodic outbreaks of infection in children worldwide and most prominently in the asia-pacific region. understanding the pathogenesis of enterovirus 71 (ev71) is hampered by the virus's inability to infect small animals and replicate in their derived in vitro cultured cells. this manuscript describes the phenotypic and genotypic characteristics of two selected ev71 strains (ev71:tllm and ev71:tllmv), which have been adapted ...201424671184
protection against lethal enterovirus 71 challenge in mice by a recombinant vaccine candidate containing a broadly cross-neutralizing epitope within the vp2 ef loop.human enterovirus 71 (ev71) is the main causative agent of hand, foot, and mouth disease (hfmd) and is associated with several severe neurological complications in the asia-pacific region. here, we evaluated that while passive transfer of neutralizing monoclonal antibody (nmab) against the vp2 protein protect against lethal ev71 infection in balb/c mice. protective nmab were mapped to residues 141-155 of vp2 by peptide elisa. high-resolution structural analysis showed that the epitope is part of ...201424669278
quality control and evaluation of vaccines in china.i was born in luoyang in 1963, a city in china with thousands of years' history. the city is the eastern starting point of the silk road (bc 206-260 ad), a famous and long trade route in human history. living in this ancient city, i grew up under the influence and impact of chinese traditional culture. when i was a teenager, i once read a book "yellow emperor's inner canon" (huang di nei jing, written about 5th century bc), which is the oldest extant classic of traditional chinese medicine. i wa ...201424663039
enterovirus 71 related severe hand, foot and mouth disease outbreaks in south-east asia: current situation and ongoing challenges. 201424652348
sybr green real-time pcr for the detection of all enterovirus-a71 genogroups.enterovirus a71 (ev-a71) has recently become an important public health threat, especially in south-east asia, where it has caused massive outbreaks of hand, foot and mouth disease every year, resulting in significant mortality. rapid detection of ev-a71 early in outbreaks would facilitate implementation of prevention and control measures to limit spread. real-time rt-pcr is the technique of choice for the rapid diagnosis of ev-a71 infection and several systems have been developed to detect circ ...201424651608
construction of an infectious cdna clone of enterovirus 71: insights into the factors ensuring experimental success.enterovirus 71 (ev 71) is a causative agent of mild hand foot and mouth disease but is capable of causing severe complications in the cns in young children. reverse genetics technology is currently widely used to study the pathogenesis of the virus. the aim of this work was to determine and evaluate the factors which can contribute to infectivity of ev 71 rna transcripts in vitro. two strategies, overlapping rt-pcr and long distance rt-pcr, were employed to obtain the full-length genome cdna clo ...201424361875
the mechanism of translation initiation on type 1 picornavirus iress.picornavirus type 1 iress comprise five principal domains (dii-dvi). whereas dv binds eif4g, a conserved aug in dvi was suggested to stimulate attachment of 43s ribosomal preinitiation complexes, which then scan to the initiation codon. initiation on type 1 iress also requires ires trans-acting factors (itafs), and several candidates have been proposed. here, we report the in vitro reconstitution of initiation on three type 1 iress: poliovirus (pv), enterovirus 71 (ev71), and bovine enterovirus ...201424357634
the nuclear protein sam68 is redistributed to the cytoplasm and is involved in pi3k/akt activation during ev71 infection.nuclear proteins can be triggered to be redistributed to the cytoplasm to assist with ev71 virus replication. this process is frequently involved in cellular signal transduction upon virus infection. in this study, we have demonstrated that a new nuclear protein, 68-kda src-associated in mitosis protein (sam68), was translocated to the cytoplasm and was co-localized with ev71 during virus infection. confocal microscopy and subcellular fractionation assay confirmed that virus 3c protease triggere ...201424316008
peripheral t lymphocyte subset imbalances in children with enterovirus 71-induced hand, foot and mouth disease.inflammatory mediators (i.e. cytokines) play a pivotal role in the regulation of pathophysiological processes during ev71-induced hand, foot and mouth disease (hfmd). different t cell subsets have distinct cytokine secretion profiles, and alteration in the t cell subsets frequency (imbalance) during infection leads to changed cytokine patterns. however, the effects of ev71 infection on t cell subsets were not clear. the objective of this study was to determine whether ev71-induced hfmd can be ex ...201424316007
global impact of heparin on gene expression profiles in neural cells infected by enterovirus 71.heparan sulphate mimetics, particularly heparin (hep), have previously been shown to considerably inhibit infection of enterovirus 71 (ev71) in vero cells. therefore, in this study, a genome-wide dna microarray was performed to gain insight into the mechanism(s) of action of hep against infection of a human neural cell line, sk-n-sh, with a clinical strain of ev71.201424281657
how to understand the efficacy measurements for enterovirus type 71 vaccine?the choice of endpoint was most important for an efficacy vaccine trial. the objective of this paper is to gear toward answering questions about the rationality and scientificity of the primary endpoints choosing, case capturing and diagnosis strategy in our recently reported ev71 vaccine efficacy phase 3 trial. in order to obtain both high sensitivity and specificity in the case detecting, ev71-associated disease had been chosen as primary endpoint, a broad spectrum of clinical symptoms was sur ...201424280898
development and evaluation of a real-time method of simultaneous amplification and testing of enterovirus 71 incorporating a rna internal control system.human enterovirus 71 (ev71) is a primary etiological agent of hand, foot, and mouth disease (hfmd). the associated infections have posed a serious threat to the public health. in the present study, a real-time simultaneous amplification and testing (sat) technology was developed for detecting ev71 (sat-ev71). the rna of ev71 and an internal control (ic) were amplified and analyzed simultaneously by isothermal amplification and real-time detection of fluorescence using routine real-time pcr. furt ...201424269796
a 3c(pro)-dependent bioluminescence imaging assay for in vivo evaluation of anti-enterovirus 71 agents.enterovirus 71 (ev71), a member of picornaviridae, is one of the major pathogens of human hand, foot and mouth disease. ev71 mainly infects children and causes severe neurological complications and even death. the pathogenesis of ev71 infection is largely unknown, and no clinically approved vaccine or effective treatment is available to date. here we described a novel bioluminescence imaging approach for ev71 detection. in this approach, a plasmid-based reporter was constructed to express the fu ...201424263113
modification of picornavirus genomic rna using 'click' chemistry shows that unlinking of the vpg peptide is dispensable for translation and replication of the incoming viral rna.picornaviruses constitute a large group of viruses comprising medically and economically important pathogens such as poliovirus, coxsackievirus, rhinovirus, enterovirus 71 and foot-and-mouth disease virus. a unique characteristic of these viruses is the use of a viral peptide (vpg) as primer for viral rna synthesis. as a consequence, all newly formed viral rna molecules possess a covalently linked vpg peptide. it is known that vpg is enzymatically released from the incoming viral rna by a host p ...201424243841
clinico-radiological spectrum in enterovirus 71 infection involving the central nervous system in children.enterovirus 71 infection causes hand, foot and mouth disease in children, and can produce diverse neurologic complications. epidemics occurring in korea between 2009 and 2012 resulted in the death of some patients. the present study aimed to clarify the correlation between clinical features and mri findings in patients presenting with acute neurologic manifestations related to enterovirus 71 infection. based on their clinical features, the patients were classified into four clinical groups: (1) ...201424169271
enterovirus 71 pathogenicity in monkeys and cotton rats.enterovirus 71 (ev71) is a neurovirulent non-polio enterovirus that can cause severe central nervous system (cns) infection in infants. vervet monkeys infected intracerebrally or intramuscularly with ev71 isolates from the bulgarian outbreak of 1975 developed clinical manifestations and pathological signs of encephalomyelitis and spinal poliomyelitis that were similar to ev71 neuroinfection in children. in addition, vervet monkeys with encephalomyelitis had severe alterations in the choroid plex ...201424158347
the population-based health effect of hand, foot and mouth disease in children in shanghai.an effective enterovirus 71 (ev71) vaccine is needed to control the annual outbreaks of hand, foot and mouth disease (hfmd) in china. adequate epidemiologic data relating to hfmd are needed to make decisions about appropriate public health interventions and implementation of the new ev71 vaccine.201424153009
evaluation of the stability of enterovirus 71 virus-like particle.enterovirus 71 (ev71) is responsible for the outbreaks of hand-foot-and-mouth disease that caused significant mortality in children, but no vaccine is available yet. ev71 virus-like particle (vlp) is the empty capsid consisting of viral structural proteins but can elicit potent immune responses, rendering vlp a promising ev71 vaccine candidate. to evaluate whether vlp remains stable after long-term storage, which is crucial for advancing the vlp vaccine to the clinical setting, we evaluated the ...201424140131
association of functional polymorphisms in the mxa gene with susceptibility to enterovirus 71 infection.myxovirus resistance a (mxa) is an antiviral protein induced by type i interferons α and β (ifn-α and ifn-β) that can inhibit virus replication. we examined whether the mxa polymorphisms were related to the risk and severity of enterovirus 71 (ev71) infection in chinese populations. the mxa c-123a and g-88t polymorphisms were genotyped in two independent case-control populations in china by polymerase chain reaction-based restriction fragment length polymorphism (pcr-rflp) analysis. multivariate ...201424085612
immunogenicity, safety, and immune persistence of a novel inactivated human enterovirus 71 vaccine: a phase ii, randomized, double-blind, placebo-controlled trial.vaccination is considered a top priority for the control of human enterovirus 71 (ev71) infection outbreaks.201423922377
elevation of human leukocyte antigen-g expression is associated with the severe encephalitis associated with neurogenic pulmonary edema caused by enterovirus 71.enterovirus 71 (ev71) infection can develop devastating clinical outcomes such as brain stem encephalitis (be) and pulmonary edema (pe). alteration of human leukocyte antigen-g (hla-g) expression or cytokine production was considered playing important roles in virus-related pathogenesis. however, clinical relevance of hla-g in ev71 infection remains unknown. in the current study, patients were stratified by disease severity as be (n = 107) and pe (n = 18). hla-g expression on peripheral blood mo ...201423605689
chimeric virus-like particle vaccines displaying conserved enterovirus 71 epitopes elicit protective neutralizing antibodies in mice through divergent mechanisms.enterovirus 71 (ev71) is a major causative agent of hand, food, and mouth disease, which frequently occurs in young children. since there are 11 subgenotypes (a, b1 to b5, and c1 to c5) within ev71, an ev71 vaccine capable of protecting against all of these subgenotypes is desirable. we report here the vaccine potential and protective mechanism of two chimeric virus-like particles (vlps) presenting conserved neutralizing epitopes of ev71. we show that fusions of hepatitis b core antigen (hbc) wi ...201424131712
epidemiology of enterovirus 71 infections in taiwan.enterovirus 71 (ev71) was first described in usa in 1969 but retrospective studies in the netherlands further detected ev71 in the clinical specimens collected in 1963. ev71 has one single serotype measured by using hyperimmune animal antisera but can be phylogenetically classified into three genogroups (a, b, and c) including 11 genotypes (a, b1-b5, c1-c5). in taiwan, ev71 caused a large-scale nationwide epidemic in 1998. retrospective studies further detected ev71 in clinical specimens collect ...201424120535
the enteroviruses: problems in need of treatments.specific antiviral therapy is currently not available for enterovirus (ev) infections. poliomyelitis, ev 71 neurologic disease, and neonatal ev disease are three manifestations of ev infections that exemplify the importance of developing antivirals for ev infections. despite tremendous strides in the effort to eradicate polio through vaccination, challenges remain, including the potential for transmission of neurovirulent vaccine-derived polioviruses which have genetically reverted from live-att ...201424119825
impact of extracorporeal membrane oxygenation support on clinical outcome of pediatric patients with acute cardiopulmonary failure: a single-center experience.conventional therapy against acute pediatric cardiopulmonary failure (apcpf) caused by a variety of disease entities remains unsatisfactory with extremely high morbidity and mortality. for refractory apcpf, extracorporeal membrane oxygenation (ecmo) is one of the last resorts.201423515152
neutralization of five subgenotypes of enterovirus 71 by taiwanese human plasma and taiwanese plasma derived intravenous immunoglobulin.enterovirus 71 (ev71) commonly occurs in children, causing hand, foot and mouth disease (hfmd) in about 29% of patients. studies have suggested that patients develop meningitis and encephalopathy with a mortality rate of 4-26%. ev71 subgenotypes including b4, b5, c2, c4 and c5 have caused hfmd epidemics in taiwan. in terms of therapeutical strategy, intravenous immunoglobulin (ivig) has been shown to improve patient conditions. in this study, the ev71 neutralizing titer was evaluated in 75 human ...201323515089
calcium flux and calpain-mediated activation of the apoptosis-inducing factor contribute to enterovirus 71-induced apoptosis.enterovirus 71 (ev71) is a causative agent of an array of childhood diseases with severe neurological manifestations implicated. ev71 infection is known to induce caspase-dependent apoptosis in cell cultures and animal models. however, whether an alternative apoptotic pathway independent of caspase activation can be triggered by ev71 infection has not been explored. in this study, we showed that calcium (ca²⁺)-activated calpains are capable of mediating caspase-independent pathway activation dur ...201323515028
structure of human enterovirus 71 in complex with a capsid-binding inhibitor.human enterovirus 71 is a picornavirus causing hand, foot, and mouth disease that may progress to fatal encephalitis in infants and small children. as of now, no cure is available for enterovirus 71 infections. small molecule inhibitors binding into a hydrophobic pocket within capsid viral protein 1 were previously shown to effectively limit infectivity of many picornaviruses. here we report a 3.2-å-resolution x-ray structure of the enterovirus 71 virion complexed with the capsid-binding inhibit ...201323509286
crystal structure of enterovirus 71 rna-dependent rna polymerase complexed with its protein primer vpg: implication for a trans mechanism of vpg uridylylation.picornavirus rna replication is initiated by vpg uridylylation, during which the hydroxyl group of the third tyrosine residue of the virally encoded protein vpg is covalently linked to two ump molecules by rna-dependent rna polymerase (rdrp; also known as 3d(pol)). we previously identified site 311, located at the base of the palm domain of the enterovirus 71 (ev71) rdrp, to be the site for ev71 vpg binding and uridylylation. here we report the crystal structure of ev71 3d(pol) complexed with vp ...201323487447
display of the viral epitopes on lactococcus lactis: a model for food grade vaccine against ev71.in this study, we have developed a system for display of antigens of enterovirus type 71 (ev71) on the cell surface of l. lactis. the viral capsid protein (vp1) gene from a local viral isolate was utilized as the candidate vaccine for the development of oral live vaccines against ev71 using l. lactis as a carrier. we expressed fusion proteins in e. coli and purified fusion proteins were incubated with l. lactis. we confirmed that mice orally fed with l. lactis displaying these fusion proteins on ...201323476790
cross-reactive neutralizing antibody responses to enterovirus 71 infections in young children: implications for vaccine development.recently, enterovirus 71 (ev71) has caused life-threatening outbreaks involving neurological and cardiopulmonary complications in asian children with unknown mechanism. ev71 has one single serotype but can be phylogenetically classified into 3 main genogroups (a, b and c) and 11 genotypes (a, b1∼b5 and c1∼c5). in taiwan, nationwide ev71 epidemics with different predominant genotypes occurred in 1998 (c2), 2000-2001 (b4), 2004-2005 (c4), and 2008 (b5). in this study, sera were collected to measur ...201323459633
neutralizing antibodies induced by recombinant virus-like particles of enterovirus 71 genotype c4 inhibit infection at pre- and post-attachment steps.enterovirus 71 (ev71) is a major causative agent of hand, foot and mouth disease, which has been prevalent in asia-pacific regions, causing significant morbidity and mortality in young children. antibodies elicited by experimental ev71 vaccines could neutralize infection in vitro and passively protect animal models from lethal challenge, indicating that neutralizing antibodies play an essential role in protection. however, how neutralizing antibodies inhibit infection in vitro remains unclear.201323451250
human scarb2 transgenic mice as an infectious animal model for enterovirus 71.enterovirus 71 (ev71) and coxsackievirus (cva) are the most common causative factors for hand, foot, and mouth disease (hfmd) and neurological disorders in children. lack of a reliable animal model is an issue in investigating ev71-induced disease manifestation in humans, and the current clinical therapies are symptomatic. we generated a novel ev71-infectious model with hscarb2-transgenic mice expressing the discovered receptor human scarb2 (hscarb2). the challenge of hscarb2-transgenic mice wit ...201323451246
complete genome analysis of the c4 subgenotype strains of enterovirus 71: predominant recombination c4 viruses persistently circulating in china for 14 years.genetic recombination is a well-known phenomenon for enteroviruses. to investigate the genetic characterization and the potential recombination of enterovirus 71 (ev71) circulating in china, we determined the 16 complete genome sequences of ev71 isolated from hand foot mouth disease (hfmd) patients during the large scale outbreak and non-outbreak years since 1998 in china. the full length genome sequences of 16 chinese ev71 in present study were aligned with 186 genome sequences of ev71 availabl ...201323441179
the interplays between autophagy and apoptosis induced by enterovirus 71.enterovirus 71 (ev71) is the causative agent of human diseases with distinct severity, from mild hand, foot and mouth disease to severe neurological syndromes, such as encephalitis and meningitis. the lack of understanding of viral pathogenesis as well as lack of efficient vaccine and drugs against this virus impedes the control of ev71 infection. ev71 virus induces autophagy and apoptosis; however, the relationship between ev71-induced autophagy and apoptosis as well as the influence of autopha ...201323437282
subneutralizing antibodies to enterovirus 71 induce antibody-dependent enhancement of infection in newborn mice.antibody-dependent enhancement (ade) of virus infections can be induced by subneutralizing concentrations of specific antibodies. we recently demonstrated ade in human monocytes infected with enterovirus 71 (ev71). the current study was designed to extend these observations by determining the effect of ade on the pathogenesis of ev71 infection in newborn mice. we compared the clinical manifestations, mortality, virus titer, histopathology, and serum levels of cytokines and chemokines in newborn ...201323408291
antiviral activity of isatis indigotica root-derived clemastanin b against human and avian influenza a and b viruses in vitro.clemastanin b, 7s,8r,8'r-(-)-lariciresinol-4,4'-bis-o-β-d-glucopyranoside, is one of the major lignans extracted from isatis indigotica root (iir). in this study, the anti-influenza activities of clemastanin b were evaluated in vitro. clemastanin b was found to inhibit different subtypes of human (h1n1, including swine-origin h1n1; h3n2 and influenza b) and avian influenza viruses (h6n2, h7n3, h9n2) at different magnitudes of activity (ic50 0.087-0.72 mg/ml) while this compound was inactive agai ...201323403777
efficacy of alcohols and alcohol-based hand disinfectants against human enterovirus 71.human enterovirus 71 (hev71) infections are a significant public health threat in the asia-pacific region and occasionally cause severe neurological complications and even death in children. although good hand hygiene is important for controlling infection, relevant data regarding the efficacy of widely used hand disinfectants against hev71 are still lacking.201323399482
recombinant baculovirus associated with bilosomes as an oral vaccine candidate against hev71 infection in mice.human enterovirus 71 (hev71) is one of the major pathogen responsible for hand, foot and mouth disease (hfmd). currently no effective vaccine or antiviral drugs are available. like poliovirus, ev71 is transmitted mainly by the feco-oral route. to date the majority of the studied ev71 vaccine candidates are administered parenterally. injectable vaccines induce good systemic immunity but mucosal responses are often unsatisfactory, whereas mucosal vaccines provide both systemic and mucosal immunity ...201323390538
hexamethonium reverses the lethal cardiopulmonary damages in a rat model of brainstem lesions mimicking fatal enterovirus 71 encephalitis.among enterovirus 71 infections, brainstem encephalitis progressing abruptly to cardiac dysfunction and pulmonary edema causes rapid death within several hours. however, no currently known early indicators and treatments can monitor or prevent the unexpectedly fulminant course. we investigate the possible mechanisms and treatment of fatal enterovirus 71 infections to prevent the abrupt progression to cardiac dysfunction and pulmonary edema by using an animal model.201323388515
development of a sensitive and specific epitope-blocking elisa for universal detection of antibodies to human enterovirus 71 strains.human enterovirus 71 (ev71) is a common cause of hand, foot and mouth disease (hfmd) in young children. it is often associated with severe neurological diseases and mortalities in recent outbreaks across the asia pacific region. currently, there is no efficient universal antibody test available to detect ev71 infections.201323383215
study of the integrated immune response induced by an inactivated ev71 vaccine.enterovirus 71 (ev71), a major causative agent of hand-foot-and-mouth disease (hfmd), causes outbreaks among children in the asia-pacific region. a vaccine is urgently needed. based on successful pre-clinical work, phase i and ii clinical trials of an inactivated ev71 vaccine, which included the participants of 288 and 660 respectively, have been conducted. in the present study, the immune response and the correlated modulation of gene expression in the peripheral blood mononuclear cells (pbmcs) ...201323372725
inhibition of enterovirus 71 infections and viral ires activity by fructus gardeniae and geniposide.fructus gardeniae has long been used by traditional chinese medical practitioners for its anti-inflammatory, anti-oxidant, anti-tumor and anti-hyperlipidemic characteristics. here we describe our finding that f. gardeniae greatly reduces anti-enterovirus 71 (ev71) activity, resulting in significant decreases in ev71 virus yields, ev71 infections, and internal ribosome entry site activity. we also found that geniposide, a primary f. gardeniae component, inhibited both ev71 replication and viral i ...201323353754
immunogenicity and safety of an enterovirus 71 vaccine in healthy chinese children and infants: a randomised, double-blind, placebo-controlled phase 2 clinical trial.enterovirus 71 (ev71) outbreaks are a socioeconomic burden, especially in the western pacific region. results of phase 1 clinical trials suggest an ev71 vaccine has a clinically acceptable safety profile and immunogenicity. we aimed to assess the best possible dose and formulation, immunogenicity, and safety profile of this ev71 vaccine in healthy chinese children.201323352749
enterovirus 71 infection cleaves a negative regulator for viral internal ribosomal entry site-driven translation.far-upstream element-binding protein 2 (fbp2) is an internal ribosomal entry site (ires) trans-acting factor (itaf) that negatively regulates enterovirus 71 (ev71) translation. this study shows that ev71 infection cleaved fbp2. live ev71 and the ev71 replicon (but not uv-inactivated virus particles) induced fbp2 cleavage, suggesting that viral replication results in fbp2 cleavage. the results also showed that virus-induced proteasome, autophagy, and caspase activity co-contribute to ev71-induced ...201323345520
breastfeeding, previous epstein-barr virus infection, enterovirus 71 infection, and rural residence are associated with the severity of hand, foot, and mouth disease.severe hand, foot, and mouth disease (hfmd) is likely to develop critical complications such as brainstem encephalitis, acute pulmonary edema, and circulatory failure, which cause child mortality during outbreaks. this study aims to investigate factors that predict the severity of hfmd. one hundred sixteen in-patient children with severe hfmd and 202 with mild hfmd were retrospectively enrolled. potential factors were collected for each child including sex, age, residence, modes of delivery, bir ...201323344210
excretion of enterovirus 71 in persons infected with hand, foot and mouth disease.hand, foot and mouth disease (hfmd) is a common illness in young children. it also can be seen in adults occasionally. enterovirus 71 (ev71), a pathogen that causes not only hfmd but also neurological complications and even death, has caused many hfmd outbreaks in china. however, till now the data about the duration of ev71 shedding is very limited.201323343115
strategies to develop antivirals against enterovirus 71.enterovirus 71 (ev71) is an important human pathogen which may cause severe neurological complications and death in children. the virus caused several outbreaks in the asia-pacific region during the past two decades and has been considered a significant public health problem in the post-poliovirus eradication era. unlike poliovirus, there is no effective vaccine or approved antivirals against ev71. to explore anti-ev71 agents therefore is of vital importance. several strategies have been employe ...201323339605
functional comparison of scarb2 and psgl1 as receptors for enterovirus 71.human scavenger receptor class b, member 2 (scarb2), and p-selectin glycoprotein ligand-1 (psgl1) have been identified to be the cellular receptors for enterovirus 71 (ev71). we compared the ev71 infection efficiencies of mouse l cells that expressed scarb2 (l-scarb2) and psgl1 (l-psgl1) and the abilities of scarb2 and psgl1 to bind to the virus. l-scarb2 cells bound a reduced amount of ev71 compared to l-psgl1 cells. however, ev71 could infect l-scarb2 cells more efficiently than l-psgl1 cells. ...201323302872
rupintrivir is a promising candidate for treating severe cases of enterovirus-71 infection: evaluation of antiviral efficacy in a murine infection model.enterovirus-71 (ev71) infections can cause life-threatening diseases with neurological symptoms. currently, no direct targeting antivirals are available to combat severe ev71 infection. rupintrivir (ag7088) is a compound originally designed for rhinovirus 3c protease. previous computational analyses by us and crystallography studies by others suggested that rupintrivir is also a high affinity inhibitor to ev71 3c. thus, we aimed to further evaluate its anti-ev71 activity in vivo at clinically ac ...201323295352
enterovirus 71 infection increases expression of interferon-gamma-inducible protein 10 which protects mice by reducing viral burden in multiple tissues.enterovirus 71 (ev71) infection has induced fatal encephalitis in thousands of young children in the asia-pacific region over the last decade. ev71 infection continues to cause serious problems in areas with outbreaks, because vaccines and antiviral therapies are not available. lymphocytes are present in the brains of infected patients and mice, and they protect mice from infection by decreasing the viral burden. the chemokines responsible for recruiting lymphocytes to infected organs are yet to ...201323288420
antiviral drug discovery for the treatment of enterovirus 71 infections.enterovirus 71 (ev71) is a small, positive-sense, single-stranded rna virus in the genus enterovirus, family picornavirus. it causes hand, foot and mouth disease in infants and children, which in a small percentage of cases progresses to central nervous system infection, ranging from aseptic meningitis to fatal encephalitis. sporadic cases of ev71 infection occur throughout the world, but large epidemics have occurred recently in southeast asia and china. there are currently no approved vaccines ...201323261847
human enterovirus 71 strains in the background population and in hospital patients in finland.human enterovirus 71 (hev71) is a common cause of severe outbreaks of hand-foot- and mouth disease, aseptic meningitis and encephalitis in asian populations but has not caused such epidemics in all populations.201323261080
progress on the research and development of human enterovirus 71 (ev71) vaccines.enterovirus 71 (ev71) infections, which can cause severe complications, have become one of the serious public health issues in the western pacific region and china. to date, a number of pharmaceutical companies and institutes have initiated the research and development of ev71 vaccines as a countermeasure. as is the case with innovative vaccine development, there are several critical bottlenecks in ev71 vaccine development that must be overcome before the clinical trials, including the selection ...201323247645
human enterovirus 71 epidemics: what's next?human enterovirus 71 (ev71) epidemics have affected various countries in the past 40 years. ev71 commonly causes hand, foot and mouth disease (hfmd) in children, but can result in neurological and cardiorespiratory complications in severe cases. genotypic changes of ev71 have been observed in different places over time, with the emergence of novel genotypes or subgenotypes giving rise to serious outbreaks. since the late 1990s, intra- and inter-typic recombination events in ev71 have been increa ...201324119538
immunogenicity, safety, and lot consistency of a novel inactivated enterovirus 71 vaccine in chinese children aged 6 to 59 months.the determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (ev71) vaccine. a phase iii, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the ev71 vaccine in children aged 6 to 59 months. healthy children (n = 1,400) received one of three lots of the ev71 vaccine containing 400 u of ev71 antigen or a placebo at days 0 and 28. blood samples were co ...201324108780
chlorogenic acid inhibits the replication and viability of enterovirus 71 in vitro.enterovirus 71 (ev71) is an etiology for a number of diseases in humans. traditional chinese herbs have been reported to be effective for treating ev71 infection. however, there is no report about the antiviral effects of cha against ev71. in this study, plaque reduction assay demonstrated that the inhibitory concentration 50% (ic50) of cha on ev71 replication is 6.3 µg/ml. when both cha (20 µg/ml) and ev71 were added, or added post-infection at different time points, cha was able to effectively ...201324098754
lncrna expression signatures in response to enterovirus 71 infection.outbreaks of hand, foot, and mouth disease caused by enterovirus 71 (ev71) have become considerable threats to the health of infants and young children. to identify the cellular long noncoding rnas (lncrnas) involved in the host response to ev71 infection, we performed comprehensive lncrna and mrna profiling in ev71-infected rhabdomyosarcoma cells through microarray. we observed the differential expression of more than 4800 lncrnas during infection. further analysis showed 160 regulated enhancer ...201323220233
microrna-23b inhibits enterovirus 71 replication through downregulation of ev71 vpl protein.enterovirus 71 (ev71) is one of the causative pathogens of hand-foot-and-mouth disease and effective antiviral agents and vaccines against this virus have, to date, not been available. micrornas (mirnas) are a recently discovered class of rnas with the function of post-transcriptional gene expression regulation. it has been demonstrated that mirnas play important roles in the complicated interaction network between virus and host, while few studies have explored the role of mirnas in ev71 infect ...201323594713
complete genome sequencing and analysis of six enterovirus 71 strains with different clinical phenotypes.hand, foot and mouth diseases (hfmd) caused by enterovirus 71(ev71) presents a broad spectrum of clinical manifestations ranging from mild febrile disease to fatal neurolocal disease. however, the mechanism of virulence is unknown.201323577963
a safety study of inactivated enterovirus 71 vaccine.enterovirus 71 (ev71) is one of the major causative agents for hand, foot and mouth disease (hfmd) in childhood. nowadays, hfmd or ev71 infections have already become an important public health issue throughout the world. vaccination may be the most effective measure to control the transmission of the virus. therefore, to pave ev71 vaccine into human clinical trial, in the present study a comprehensive preclinical safety assessment of inactivated ev71 vaccine including single- and repeat-dose to ...201323571172
iridoid and bis-iridoid glucosides from the fruit of gardenia jasminoides.three new iridoid glucosides, 6″-o-trans-feruloylgenipin gentiobioside (1), 2'-o-trans-caffeoylgardoside (2), jasmigeniposide a (3), and one new bis-iridoid glucoside, jasmigeniposide b (4), along with six known analogues (5-10), were isolated from the fruit of gardenia jasminoides. their structures were established on the basis of spectroscopic analyses and chemical methods. anti-virus activity of isolated compounds were evaluated in vitro and only compound 9 showed moderate inhibitory activity ...201323567862
mri characteristics of brainstem encephalitis in hand-foot-mouth disease induced by enterovirus type 71--will different mri manifestations be helpful for prognosis?the mri characteristics of 21 hfmd patients with brainstem encephalitis resulting from ev71 infection were examined to identify lesion patterns helpful in disease classification and prognosis. the author reviewed the clinical and mri data of 21 children with brainstem encephalitis infected during the ev71 outbreak in hainan, china from may 2008 to september 2010. thirteen cases of brainstem encephalitis were classified as type i based on unilateral or bilateral symmetrical patch-like hyperintens ...201323561930
immune responses to baculovirus-displayed enterovirus 71 vp1 antigen.the increased distribution and neurovirulence of enterovirus 71 is an important health threat for young children in asia pacific. vaccine design has concentrated on inactivated virus with the most advanced undergoing phase iii clinical trials. by using a subunit vaccine approach, production costs could be reduced by lowering the need for biocontainment. in addition, novel mutations could be rapidly incorporated to reflect the emergence of new enterovirus 71 subgenogroups. to circumvent the probl ...201323560917
chlorine dioxide inactivation of enterovirus 71 in water and its impact on genomic targets.to control the waterborne transmission of enterovirus 71(ev71), which is associated with hand foot and mouth disease (hfmd), it is essential to know the inactivation effectiveness of disinfectants on ev71 in water. in this article, we present a comparative analysis of the effects on ev71 following exposure to chlorine dioxide (clo2) under different doses, ph, and temperature conditions. we show that the ev71 exhibited strong resistance to clo2 (more than the ms2 standard) and that ct value range ...201323560857
the enterovirus 71 a-particle forms a gateway to allow genome release: a cryoem study of picornavirus uncoating.since its discovery in 1969, enterovirus 71 (ev71) has emerged as a serious worldwide health threat. this human pathogen of the picornavirus family causes hand, foot, and mouth disease, and also has the capacity to invade the central nervous system to cause severe disease and death. upon binding to a host receptor on the cell surface, the virus begins a two-step uncoating process, first forming an expanded, altered "a-particle", which is primed for genome release. in a second step after endocyto ...201323555253
enterovirus 71 protease 2apro targets mavs to inhibit anti-viral type i interferon responses.enterovirus 71 (ev71) is the major causative pathogen of hand, foot, and mouth disease (hfmd). its pathogenicity is not fully understood, but innate immune evasion is likely a key factor. strategies to circumvent the initiation and effector phases of anti-viral innate immunity are well known; less well known is whether ev71 evades the signal transduction phase regulated by a sophisticated interplay of cellular and viral proteins. here, we show that ev71 inhibits anti-viral type i interferon (ifn ...201323555247
a phase i, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine.large-scale outbreaks of enterovirus 71 (ev71) infections have occurred in asia-pacific regions. severe complications include encephalitis and poliomyelitis-like paralysis, cardiopulmonary collapse, and death, necessitating an effective vaccine against ev71.201323541623
beta-actin variant is necessary for enterovirus 71 replication.enterovirus 71 (ev71) is one of the main etiological agents of the hand, foot and mouth disease (hfmd) and has been known to cause fatal neurological complications such as herpangina, aseptic meningitis, poliomyelitis-like paralysis and encephalitis. ev71 is endemic in the asia-pacific region and causes occasional epidemics. in order to better understand ev71 infection, we compared the proteome between ev71-susceptible and ev71-resistant human rhabdomyosarcoma (rd) cell line. we found significan ...201323535377
association of interleukin-17f gene polymorphism with enterovirus 71 encephalitis in patients with hand, foot, and mouth disease.enterovirus 71 (ev71) is one of the common pathogenic agents of hand, foot, and mouth disease (hfmd) and is associated with severe complications including encephalitis. interleukin (il)-17f plays an important role in tissue inflammation by inducing release of proinflammatory cytokines and chemokines. we investigated the association between ev71 encephalitis and of il-17f 7488t/c (rs763780) gene polymorphism, which is known to cause a his-to-arg substitution at amino acid 161. the study was perfo ...201323519962
synthesis and antiviral activity of n-phenylbenzamide derivatives, a novel class of enterovirus 71 inhibitors.a series of novel n-phenylbenzamide derivatives were synthesized and their anti-ev 71 activities were assayed in vitro. among the compounds tested, 3-amino-n-(4-bromophenyl)-4-methoxybenzamide (1e) was active against the ev 71 strains tested at low micromolar concentrations, with ic50 values ranging from 5.7 ± 0.8-12 ± 1.2 μm, and its cytotoxicity to vero cells (tc50 = 620 ± 0.0 μm) was far lower than that of pirodavir (tc50 = 31 ± 2.2 μm). based on these results, compound 1e is a promising lead ...201323519203
ribavirin-resistant mutants of human enterovirus 71 express a high replication fidelity phenotype during growth in cell culture.it has been shown in animal models that ribavirin-resistant poliovirus with a g64s mutation in its 3d polymerase has high replication fidelity coupled with attenuated virulence. here, we describe the effects of mutagenesis in the human enterovirus 71 (hev71) 3d polymerase on ribavirin resistance and replication fidelity. seven substitutions were introduced at amino acid position 3d-g64 of a hev71 full-length infectious cdna clone (26m). viable clone-derived virus populations were rescued from th ...201323175376
cleavage of interferon regulatory factor 7 by enterovirus 71 3c suppresses cellular responses.enterovirus 71 (ev71) is a positive-stranded rna virus which is capable of inhibiting innate immunity. among virus-encoded proteins, the 3c protein compromises the type i interferon (ifn-i) response mediated by retinoid acid-inducible gene-i (rig-i) or toll-like receptor 3 that activates interferon regulatory 3 (irf3) and irf7. in the present study, we report that enterovirus 71 downregulates irf7 through the 3c protein, which inhibits the function of irf7. when expressed in mammalian cells, the ...201323175366
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