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a strain-specific epitope of enterovirus 71 identified by cryo-electron microscopy of the complex with fab from neutralizing antibody.enterovirus 71 (ev71) is a picornavirus that causes outbreaks of hand, foot, and mouth disease (hfmd), primarily in the asia-pacific area. unlike coxsackievirus a16, which also causes hfmd, ev71 induces severe neuropathology leading to high fatalities, especially among children under the age of 6 years. currently, no established vaccines or treatments are available against ev71 infection. the monoclonal antibody ma28-7 neutralizes only specific strains of ev71 that have a conserved glycine at am ...201323946455
soluble interleukin-6 receptor-mediated innate immune response to dna and rna viruses.the interleukin-6 (il-6) receptor, which exists as membrane-bound and soluble forms, plays critical roles in the immune response. the soluble il-6 receptor (sil6r) has been identified as a potential therapeutic target for preventing coronary heart disease. however, little is known about the role of this receptor during viral infection. in this study, we show that sil6r, but not il-6, is induced by viral infection via the cyclooxygenase-2 pathway. interestingly, sil6r, but not il-6, exhibited ext ...201323946454
[epidemiological and etiological characteristics of hand-foot-mouth disease in ningbo, zhejiang province, 2008-2011].to analyze the epidemiological characteristics of hand foot and mouth disease (hfmd) in ningbo.201323937841
protective efficacy of vp1-specific neutralizing antibody associated with a reduction of viral load and pro-inflammatory cytokines in human scarb2-transgenic mice.hand-foot-mouth diseases (hfmd) caused by enterovirus 71 (ev71) and coxsackievirus 16 (cva16) in children have now become a severe public health issue in the asian-pacific region. recently we have successfully developed transgenic mice expressing human scavenger receptor class b member 2 (hscarb2, a receptor of ev71 and cva16) as an animal model for evaluating the pathogenesis of enterovirus infections. in this study, hscarb2-transgenic mice were used to investigate the efficacy conferred by a p ...201323936115
enterovirus 71 binding to psgl-1 on leukocytes: vp1-145 acts as a molecular switch to control receptor interaction.some strains of enterovirus 71 (ev71), but not others, infect leukocytes by binding to a specific receptor molecule: the p-selectin glycoprotein ligand-1 (psgl-1). we find that a single amino acid residue within the capsid protein vp1 determines whether ev71 binds to psgl-1. examination of capsid sequences of representative ev71 strains revealed that the psgl-1-binding viruses had either a g or a q at residue 145 within the capsid protein vp1 (vp1-145g or q), whereas psgl-1-nonbinding viruses ha ...201323935488
patterns of polymorphism and divergence in the vp1 gene of enterovirus 71 circulating in the asia-pacific region between 1994 and 2013.enterovirus 71 has been implicated in several outbreaks of hand, foot and mouth disease in the asia-pacific region. the present study aimed to achieve comprehensive evolutionary dynamic aspects of ev71 during 1994-2013, based on phylogenetic analyses of the vp1 sequences. the results indicated that 4 genotypes, namely c4, c1, c2 and b4 are the predominant strains, especially in southeast asian countries. no common ancestor was shared in different countries. fourteen sites of substitutions were d ...201323933074
plasma b-type natriuretic peptide study in children with severe enterovirus 71 infection: a pilot study.severe enterovirus 71 (ev71) infections in children can result in acute heart failure. b-type natriuretic peptide (bnp) is a good biomarker of myocardial stress. the purpose of this study was to use plasma bnp for the detection of ev71 infection with cardiac involvement.201323932576
[retrospective analysis of clinical and epidemiological characteristics of hand-foot-and-mouth disease deceased cases in zhejiang province].to understand the clinical and epidemiological characteristics of hand-foot-and-mouth disease (hfmd) deceased cases.201323927799
genetic and antigenic characterization of enterovirus 71 in ho chi minh city, vietnam, 2011.enterovirus 71 (ev71) frequently causes fatal infections in young children in asia. in 2011, ev71 epidemics occurred in southern vietnam. we conducted genetic and antigenic analysis of the ev71 isolates and found that 94% of them were genotype c4a related to two lineages circulating in china and 6% were genotype c5 which have circulated in vietnam since 2003. antigenic variants were not detected. ev71 vaccines are being developed. longitudinal enterovirus surveillance data are critical to formul ...201323922846
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
novel cycloalkylthiophene-imine derivatives bearing benzothiazole scaffold: synthesis, characterization and antiviral activity evaluation.a series of novel cycloalkylthiophene-imine derivatives containing benzothiazole unit were designed, synthesized and evaluated for their anti-viral activities. the bio-evaluation results indicated that some of the target compounds (such as 5g, 5i, 5u) exhibited good to moderate antiviral effect on cvb5, adv7 and ev71 viruses, however, these compounds did not have inhibition activity against h1n1 virus. especially, the compounds 4c and 4d also exhibited high antiviral activities, which provide a ...201323920438
establishment of cell lines with increased susceptibility to ev71/ca16 by stable overexpression of scarb2.human enterovirus type 71 (ev71) and coxsackievirus a group type 16 (ca16) belong to human enterovirus species a of the family picornaviridae. these viruses are recognized as the major pathogens responsible for epidemics of hand-foot-mouth disease (hfmd), which presents with fever and vesicular eruptions of palms, soles of the feet or mouth. human scavenger receptor class b, member 2 (scarb2) has been identified as the receptor for both ev71 and ca16, as overexpression of scarb2 in cells can enh ...201323919614
development of duplex real-time rt-pcr based on taqman technology for detecting simultaneously the genome of pan-enterovirus and enterovirus 71.human enterovirus (ev) 71 is the main etiological agent of hand, foot, and mouth disease (hfmd). it is associated with neurological complications, and caused fatalities during recent outbreaks in the asia-pacific region. infections caused by ev71 could lead to many complications, ranging from brainstem encephalitis to pulmonary oedema, resulting in high mortality. in this study, a duplex real-time rt-pcr assay was developed in order to simultaneously detect pan-ev and ev71. ev71-specific primers ...201323918544
changing aetiology of hand, foot and mouth disease in linyi, china, 2009-2011.millions of hand, foot and mouth disease cases occur annually and the disease is considered a significant public health threat in china. we have focused on linyi for 3 years to analyse the aetiological spectrum and epidemic changes. the reported number of cases of hfmd in linyi declined in 2011,with the percentage of hev71 dropping to 11%. although cva16 rose to 51% in 2011, the number of cva16 cases did not change significantly compared with the previous 2 years. other types of enteroviruses we ...201423910234
[the pathogenic spectrum of hand, foot and mouth disease and molecular characterizations of human enterovirus 71 in inner mongolia autonomous region in 2010].to study the pathogenic spectrum of hand, foot and mouth disease (hfmd) and the molecular characterizations of human enteroviruses 71 (hev71) isolated from the clinical specimens of hfmd patients in inner mongolia in 2010. a total of 921 clinical specimens including stools and throat swabs were collected from hfmd patients in outpatient service in inner mongolia and then viral isolation was performed, the positive viral isolates were identified by using the real-time pcr method (detecting ev, he ...201323905475
[recombination analysis of enterovirus 71 strain isolated in guangzhou, 2009].to describe the recombination features of human enterovirus 71 strain guangzhou09 isolated in guangzhou in 2009, the complete nucleotide sequences of guangzhou09 were analyzed by various of bioinformatics software. phylogenetic analysis based on p1, p2 and p3 regions indicated that recombination occurred between ev71 and cva4. phylogenetic, similarity plot and bootscan analysis further revealed the recombination between ev71 genotype c strain shanghai-fj713317 and cva4 strain hq728260 at region ...201323905474
[the 2a protease of enterovirus 71 cleaves nup62 to inhibit nuclear transport].to study the impact of the enterovirus 71(ev71) on the nuclear transport mechanism,the pgfp-nls vector with nuclear location signal(nls) was constructed, rd cells transfected by the pgfp-nls vector were inoculated with the ev71 or cotransfected by ev71-2a vector. the results showed that gfp protein with nls was expressed in the cytoplasm due to the inhibition of nuclear transport. in order to further study the mechanism of the ev71 to prevent nuclear transport,nup62 was detected by western blott ...201323895008
[research on human enterovirus 71 infectivity assay based on a real-time cell analysis].this research aims to evaluate the application of real - time cell assay (rtca) based on microelectronics sensor technology in the detection of hev71 induced cell lesion. growth indexes of rd cells at different stages were observed dynamically, appropriate cell concentration was selected to test hev71 infectivity and to determine the hev71 neutralizing antibody titer in serum. the traditional microplate test was used as methodology comparison and results validation at the same time. cell impedan ...201323895003
elevated antigen-specific th2 type response is associated with the poor prognosis of hand, foot and mouth disease.the immunopathogenesis of severe hand, foot and mouth disease (hfmd) remains elusive. this study revealed that enterovirus 71 (ev71) epitope-specific cd4+ t cell responses of hfmd patients were skewed toward a th2 cytokine profile. patients that demonstrated higher levels of il-4 expression in their cd4 t cells following antigen stimulation in vitro tended to have a more prolonged period of high fevers and a longer duration of illness. thus, an increase of ev71 epitope-specific th2 type response ...201323886670
autoprocessing: an essential step for expression and purification of enterovirus 71 3c(pro) in escherichia coli.a gene encoding the 3bc of human enterovirus 71 (ev71) was cloned and inserted into a derivative of plasmid pet-32a(+) driven by t7 promoter. the expressed 3c protease (3c(pro)) autocatalytically cleaved itself from the recombinant protein trx-3bc and the mature 3c(pro) partitioned in the soluble fraction of bacterial lysate. the 13-amino-acid peptide substrates with the junction of 3b/3c were used to verify the proteolysis activity of the purified 3c(pro). the ev71 3c(pro) had a km value of 63 ...201323881322
fatal case of enterovirus 71 infection and rituximab therapy, france, 2012. 201323880543
construction and characterization of an infectious cdna clone of enterovirus type 71 subgenotype c4.enterovirus 71 (ev71) is the major causative agent of hand, foot, and mouth disease and induces fatal neurological complications. in recent years, this virus has become a major threat to public health in the asia-pacific region, while no effective antiviral therapies and vaccines are currently available. in this study, we constructed and characterized for the first time an infectious full-length ev71 cdna clone derived from the shzh98 strain, which was the first subgenotype c4 strain isolated in ...201323877719
accuracy of diagnostic methods and surveillance sensitivity for human enterovirus, south korea, 1999-2011.the epidemiology of enteroviral infection in south korea during 1999-2011 chronicles nationwide outbreaks and changing detection and subtyping methods used over the 13-year period. of 14,657 patients whose samples were tested, 4,762 (32.5%) samples were positive for human enterovirus (human ev); as diagnostic methods improved, the rate of positive results increased. a seasonal trend of outbreaks was documented. genotypes enterovirus 71, echovirus 30, coxsackievirus b5, enterovirus 6, and coxsack ...201323876671
characterisation of enterovirus 71 replication kinetics in human colorectal cell line, ht29.hand, foot and mouth disease (hfmd), a contagious viral disease that commonly affects infants and children with blisters and flu like symptoms, is caused by a group of enteroviruses such as enterovirus 71 (ev71) and coxsackievirus a16 (ca16). however some hfmd caused by ev71 may further develop into severe neurological complications such as encephalitis and meningitis. the route of transmission was postulated that the virus transmit from one person to another through direct contact of vesicular ...201323875129
complete genome sequence of a human enterovirus 71 strain isolated in brunei in 2006.the complete genome sequence of a human enterovirus 71 strain isolated in brunei in 2006 was determined. phylogenetic analysis based on the complete genome sequence classified this strain into subgenogroup b5.201323868136
vp2 dominated cd4+ t cell responses against enterovirus 71 and cross-reactivity against coxsackievirus a16 and polioviruses in a healthy population.enterovirus 71 (ev71)-associated hand-foot-mouth disease has become a major threat to public health in the asia-pacific region. although t cell immunity is closely correlated with clinical outcomes of ev71 infection, little is known about t cell immunity baseline against ev71 and t cell immunogenecity of ev71 ags in the population, which has restricted our understanding of immunoprotection mechanisms. in this study, we investigated the cellular immune responses against the four structural ags of ...201323863902
global transcriptomic analysis of human neuroblastoma cells in response to enterovirus type 71 infection.human enterovirus type 71 (ev71) is the major pathogen of hand-foot-and-mouth disease (hfmd) and has been associated with severe neurological disease and even death in infants and young children. the pathogenesis of ev71 infection in the human central nervous system remains unclear. in this study, human whole genome microarray was employed to perform transcriptome profiling in sh-sy5y human neuroblastoma cells infected with ev71. the results indicated that ev71 infection lead to altered expressi ...201323861741
a study of the virulence in mice of high copying fidelity variants of human enterovirus 71.polioviruses with a g64s mutation in the 3d polymerase have enhanced replication fidelity and are attenuated in animal models. here we describe the mouse virulence properties of high replication fidelity 3d polymerase variants of human enterovirus 71 (hev71), with mutations at positions 3d-s264l, 3d-g64r or at 3d-s264l plus 3d-g64r. mouse-adapted strains (mp-g64r, mp-s264l and mp-s264l-g64r) were constructed in order to compare the virulence of the 3d polymerase variants with that of mouse-adapt ...201323856384
seroepidemiology of human enterovirus71 and coxsackievirusa16 among children in guangdong province, china.hand, foot and mouth disease (hfmd) is a common pediatric illness. mainly induced by the enterovirus 71 and coxsackievirus a 16 infections, the frequently occurred hfmd outbreaks have become a serious public health problem in southeast asia. currently,only a few studies have investigated the human immunity to hfmd in china. in this study, we conducted a cohort study in guangdong province, china.201323855481
[2009 evolution for vp4 of enterovirus 71 strains in shenzhen].to analyze the genetic evolution for the common causative agent of hand, foot and mouth disease(hfmd) that vp4 of human enterovirus 71 in shenzhen district.201323855119
a novel enterovirus and parechovirus multiplex one-step real-time pcr-validation and clinical experience.as the number of new enteroviruses and human parechoviruses seems ever growing, the necessity for updated diagnostics is relevant. we have updated an enterovirus assay and combined it with a previously published assay for human parechovirus resulting in a multiplex one-step rt-pcr assay. the multiplex assay was validated by analysing the sensitivity and specificity of the assay compared to the respective monoplex assays, and a good concordance was found. furthermore, the enterovirus assay was ab ...201323845901
comparative study of the cytokine/chemokine response in children with differing disease severity in enterovirus 71-induced hand, foot, and mouth disease.enterovirus 71 (ev71) infection can lead to a rapidly progressing, life-threatening, and severe neurological disease in young children, including the development of human hand, foot, and mouth disease (hfmd). this study aims to further characterize the specific immunological features in ev71-mediated hfmd patients presenting with differing degrees of disease severity.201323840697
first case of severe enterovirus 71 infection in portugal. 201323838666
formulation and immunological evaluation of a trivalent vaccine comprising emulsified submicron particles and inactivated virions of h5n1/ev71/jev.combination vaccines can reduce the number of injections and simplify the immunization schedule required to prevent different diseases. here we assessed the immunogenicity in a mouse model of a vaccine composition comprising inactivated influenza viruses (h5n1/h1n1), enterovirus 71 (ev71), and/or japanese encephalitis virus (jev) and investigated whether the vaccine formulations can overcome the immunologic interference between the individual vaccine components. we demonstrated that the antigeni ...201323838466
validation-based insertional mutagenesis for identification of nup214 as a host factor for ev71 replication in rd cells.lentiviral validation-based insertional mutagenesis (vbim) is a sophisticated, forward genetic approach that is used for the investigation of signal transduction in mammalian cells. using vbim, we conducted function-based genetic screening for host genes that affect enterovirus 71 (ev71) viral replication. this included host factors that are required for the life cycle of ev71 and host restriction factors that inhibit ev71 replication. several cell clones, resistant to ev71, were produced using ...201323831628
what we are watching--five top global infectious disease threats, 2012: a perspective from cdc's global disease detection operations center.disease outbreaks of international public health importance continue to occur regularly; detecting and tracking significant new public health threats in countries that cannot or might not report such events to the global health community is a challenge. the centers for disease control and prevention's (cdc) global disease detection (gdd) operations center, established in early 2007, monitors infectious and non-infectious public health events to identify new or unexplained global public health th ...201323827387
enterovirus infection among patients admitted to hospital in hong kong in 2010: epidemiology, clinical characteristics, and importance of molecular diagnosis.the activity of hand, foot, and mouth disease (hfmd) in hong kong was high in 2010. real-time reverse transcriptase-polymerase chain reaction (rt-pcr) had been performed routinely for diagnosis of enterovirus (ev) infection among hospitals in a geographical cluster. the aim of the study was to describe the epidemiology and the clinical pattern of ev-related hospital admission in 2010, and evaluate the impact of rt-pcr compared to conventional method. this was a retrospective study and patients w ...201323824683
genetic characterization of ev71 isolates from 2004 to 2010 reveals predominance and persistent circulation of the newly proposed genotype d and recent emergence of a distinct lineage of subgenotype c2 in hong kong.enterovirus 71 (ev71) is a common etiological agent of hand, foot and mouth disease (hfmd) in children. ev71 epidemics have been reported in hong kong in recent years, and yet the genetic information of ev71 strains circulating in our locality is limited. the objective of this study was to investigate the genetic evolution of these ev71 isolates in hong kong over a 7-year period.201323822185
necrotizing myositis causes restrictive hypoventilation in a mouse model for human enterovirus 71 infection.enterovirus 71 (ev71) infections are associated with a high prevalence of hand, foot and mouth disease (hfmd) in children and occasionally cause lethal complications. most infections are self-limiting. however, resulting complications, including aseptic meningitis, encephalitis, poliomyelitis-like acute flaccid paralysis, and neurological pulmonary edema or hemorrhage, are responsible for the lethal symptoms of ev71 infection, the pathogenesis of which remain to be clarified.201323809248
atypical hand-foot-mouth disease in children: a hospital-based prospective cohort study.in 2010, we observed children with atypical presentations of hand-foot-mouth disease (hfmd), such as rashes on earlobes and faces, or bullae on trunks and bilateral limbs. hyperpigmentation later developed as the bullous lesions crusted. thus, we intended to study the etiology of the illness and the phylogeny of the pathogens.201323800163
differential gene expressions of the mapk signaling pathway in enterovirus 71-infected rhabdomyosarcoma cells.mitogen-activated protein kinase (mapk) signaling pathway plays an important role in response to viral infection. the aim of this study was to explore the function and mechanism of mapk signaling pathway in enterovirus 71 (ev71) infection of human rhabdomyosarcoma (rd) cells.201323797008
characterization of enterovirus 71 and coxsackievirus a16 isolated in hand, foot, and mouth disease patients in guangdong, 2010.hand, foot, and mouth disease (hfmd) is an acute viral disease caused by human enteroviruses, especially human enterovirus 71 (hev71) and coxsackievirus a16 (cva16), and mainly affects infants and young children. after the outbreak in 2008 in fuyang, china, hfmd was classified as a category c notifiable infectious disease by the ministry of health of china.201323791223
rapid and highly sensitive detection of enterovirus 71 by using nanogold-enhanced electrochemical impedance spectroscopy.enterovirus 71 (ev71) infection is an emerging infectious disease causing neurological complications and/or death within two to three days after the development of fever and rash. a low viral titre in clinical specimens makes the detection of ev71 difficult. conventional approaches for detecting ev71 are time consuming, poorly sensitive, or complicated, and cannot be used effectively for clinical diagnosis. furthermore, ev71 and coxsackie virus a16 (ca16) may cross react in conventional assays. ...201323787733
hand, foot, mouth, brainstem, and heart disease resulting from enterovirus 71. 201323774351
specific primer amplification of the vp1 region directed by 5' utr sequence analysis: enterovirus testing and identification in clinical samples from hand-foot-and-mouth disease patients.many genotypes of the enterovirus (ev) pathogens can cause clinical hand-foot-and-mouth disease (hfmd). therefore, rapid identification and monitoring of hfmd pathogens can be difficult, especially from the original clinical specimens. in this study, both universal pan-enterovirus and ev71/ca16 vp1-specific primer sets were designed and used to examine clinical specimens from hfmd patients. based on the initial sequence analysis of the 5'-untanslated region (5'-utr) and vp1 amplification product ...201323769858
caveolar endocytosis is required for human psgl-1-mediated enterovirus 71 infection.enterovirus 71 (ev71) causes hand, foot, and mouth disease and severe neurological disorders in children. human scavenger receptor class b member 2 (hscarb2) and p-selectin glycoprotein ligand-1 (psgl-1) are identified as receptors for ev71. the underling mechanism of psgl-1-mediated ev71 entry remains unclear. the endocytosis required for ev71 entry were investigated in jurkat t and mouse l929 cells constitutively expressing human psgl-1 (psgl-1-l929) or human rhabdomyosarcoma (rd) cells displa ...201323760234
[progress in research of new human enterovirus types].more and more new human enteroviruses (hevs) types were identified with the broad application of the molecular serotyping methods for enteroviruses. since enterovirus 71 (ev71) was first reported in 1969, numerous epidemic outbreaks associated with new enteroviruses have occurred all around the world, and pose a significant threat to public health . the epidemics of hand, foot and mouth disease (hfmd) caused by ev71 infection in china have raised great concern of global scholars. this paper revi ...201323757855
[analysis on molecular epidemiological features of enterovirus type 71 in guizhou province, 2008-2011].to study the genotype and molecular epidemiological features of enterovirus type 71 (ev71) in guizhou province. the hand-foot-mouth disease(hfmd) patients since 2008 in guizhou province were surveyed. ev71 rna positive samples, including mild cases, death cases and cases of serious conditions, were used for subsequent cell culture and sequencing of vp1 complete gene. genotypes were compared between domestic and foreign epidemic strains. the results showed that the main pathogenwas ev71 subtype c ...201323757849
development and evaluation of a pseudovirus-luciferase assay for rapid and quantitative detection of neutralizing antibodies against enterovirus 71.the level of neutralizing antibodies (ntab) induced by vaccine inoculation is an important endpoint to evaluate the efficacy of ev71 vaccine. in order to evaluate the efficacy of ev71 vaccine, here, we reported the development of a novel pseudovirus system expression firefly luciferase (pvla) for the quantitative measurement of ntab. we first evaluated and validated the sensitivity and specificity of the pvla method. a total of 326 serum samples from an epidemiological survey and 144 serum speci ...201323755115
enterovirus 71 receptors: promising drug targets? 201323750725
progress on the research and development of inactivated ev71 whole-virus vaccines.the prevalence of diseases caused by ev71 infection has become a serious public health problem in the western pacific region. due to a lack of effective treatment options, controlling ev71 epidemics has mainly focused on the research and development (r&d) of ev71 vaccines. thus far, five organizations have completed pre-clinical studies focused on the development of inactivated ev71 whole-virus vaccines, including vaccine strain screening, process optimization, safety and immunogenicity evaluati ...201323744508
development of a sandwich elisa for the quantification of enterovirus 71.since 2008, enterovirus 71 (ev71) has been responsible for high-mortality seasonal epidemics of hand, foot and mouth disease in china. currently many groups in the world are in the process of developing ev71 vaccines to combat this deadly disease. we have developed three ev71-specific monoclonal antibodies, and in this study we report the establishment of a fast and cost-effective sandwich elisa kit for measurement of virus concentration in ev71 vaccines using a pair of mouse anti-ev71 monoclona ...201423728855
high-affinity interaction of hnrnp a1 with conserved rna structural elements is required for translation and replication of enterovirus 71.human enterovirus 71 (ev71) is an emerging pathogen of infectious disease and a serious threat to public health. currently, there are no antivirals or vaccines to slow down or prevent ev71 infections, thus underscoring the urgency to better understand mechanisms of host-enterovirus interactions. ev71 uses a type i internal ribosome entry site (ires) to recruit the 40s ribosomal subunit via a pathway that requires the cytoplasmic localization of hnrnp a1, which acts as an ires trans-activating fa ...201323727900
virus-like particles for enterovirus 71 produced from saccharomyces cerevisiae potently elicits protective immune responses in mice.human enterovirus 71 (ev71) is recognized as the leading causative agent of hand-foot-and-mouth disease (hfmd) in the asia-pacific region in recent years. there are still no approved antiviral drugs or vaccines against ev71 infection yet. in this study, we have developed an advanced platform for production of the virus-like particles (vlps) for ev71 in saccharomyces cerevisiae by co-expressing p1 and 3cd genes of ev71. these vlps exhibited similar morphology and protein composition as ev71 empty ...201323726823
efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in china: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.a vaccine for enterovirus 71 (ev71) is needed to address the high burden of disease associated with infection. we assessed the efficacy, safety, immunogenicity, antibody persistence, and immunological correlates of an inactivated alum-adjuvant ev71 vaccine.201323726161
[establishment of ev71 animal models with 2-week-old balb/c mice].animal model is very important for anti-ev71 (enterovirus 71) drug and vaccine development. 1-day-old suckling ev71 mouse model is the main in vivo model used in china. 1-day-old suckling ev71 mouse is too small to perform antiviral experiment. and the route of administration and dosage capacity are also restricted. a strong virulence ev71 virus strain was selected after screening from five ev71 strains with 1-day-old suckling mice. a mouse-adapted ev71 strain with increased virulence in 12-day- ...201323724645
heat shock protein-90-beta facilitates enterovirus 71 viral particles assembly.molecular chaperones are reported to be crucial for virus propagation, but are not yet addressed in human enterovirus 71 (ev71). here we describe the specific association of heat shock protein-90-beta (hsp90β), but not alpha form (hsp90α), with ev71 viral particles by the co-purification with virions using sucrose density gradient ultracentrifugation, and by the colocalization with viral particles, as assessed by immunogold electron microscopy. the reduction of the hsp90β protein using rna inter ...201323711381
analysis and solution of false-positives when testing cva16 sera using an antibody assay against the ev71 virus.hand, foot and mouth disease (hfmd) in humans is caused mainly by enterovirus 71(ev71) and coxsackievirus a16 (cva16). ev71 is associated with severe hfmd cases but not cva16. use of igm-capture enzyme-linked immunosorbent assay (elisa) is important for the early diagnosis of ev71 infection, but cross-reactivity of the anti-cva16 igm antibody with ev71 produces false-positive results. in this report, we designed a new ev71 igm-capture elisa method using the ev71 vp1 peptide instead of the ev71 v ...201323707400
human igg subclasses against enterovirus type 71: neutralization versus antibody dependent enhancement of infection.the emerging human enterovirus 71 (ev71) represents a growing threat to public health, and no vaccine or specific antiviral is currently available. human intravenous immunoglobulin (ivig) is clinical used in treating severe ev71 infections. however, the discovery of antibody dependent enhancement (ade) of ev71 infection illustrates the complex roles of antibody in controlling ev71 infection. in this study, to identify the distinct role of each igg subclass on neutralization and enhancement of ev ...201323700449
substituted 3-benzylcoumarins as allosteric mek1 inhibitors: design, synthesis and biological evaluation as antiviral agents.in order to find novel antiviral agents, a series of allosteric mek1 inhibitors were designed and synthesized. based on docking results, multiple optimizations were made on the coumarin scaffold. some of the derivatives showed excellent mek1 binding affinity in the appropriate enzymatic assays and displayed obvious inhibitory effects on the erk pathway in a cellular assay. these compounds also significantly inhibited virus (ev71) replication in hek293 and rd cells. several compounds showed poten ...201323698055
milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial.enterovirus 71-induced brainstem encephalitis with pulmonary edema and/or neurogenic shock (stage 3b) is associated with rapid mortality in children. in a small pilot study, we found that milrinone reduced early mortality compared with historical controls. this prospective, randomized control trial was designed to provide more definitive evidence of the ability of milrinone to reduce the 1-week mortality of stage 3b enterovirus 71 infections.201323685637
robust antiviral responses to enterovirus 71 infection in human intestinal epithelial cells.enterovirus 71 (ev71) is a single-stranded rna virus that belongs to picornaviridae family. it causes the hand-foot-and-mouth disease and fatal neurological diseases in young children and infants. the mechanism of ev71 pathogenesis remains obscure. the intestinal tract is the initial site of ev71 replication, but no or only mild gastrointestinal symptoms are observed clinically, suggesting that host immune responses of the intestinal epithelium to ev71 may be unique, which, however, remains rare ...201323685430
enterovirus 71 encephalitis: a new vaccine on the horizon? 201323668563
inhibition of enveloped viruses infectivity by curcumin.curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (ha) activity. this study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. in all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. in contrast, the nonenveloped enterovirus 71 r ...201323658730
mda5 plays a crucial role in enterovirus 71 rna-mediated irf3 activation.induction of type-i interferons (ifns), ifn-α/β, is crucial to innate immunity against rna virus infection. cytoplasmic retinoic acid-inducible gene i (rig-i)-like receptors, including rig-i and melanoma differentiation-associated gene 5 (mda5), are critical pathogen sensors for activation of type-i ifn expression in response to rna virus infection. mda5 is required for type-i ifn expression in mouse models in response to infection by picornaviruses, such as encephalomyocarditis virus (emcv) and ...201323650567
chebulagic acid, a hydrolyzable tannin, exhibited antiviral activity in vitro and in vivo against human enterovirus 71.human enterovirus 71 is one of the major causative agents of hand, foot and mouth disease in children under six years of age. presently, no vaccines or antiviral drugs have been clinically available to employ against ev71. in this study, we demonstrate that treatment with chebulagic acid reduced the viral cytopathic effect on rhabdomyosarcoma cells with an ic50 of 12.5 μg/ml. the utilization of the chebulagic acid treatment on mice challenged with a lethal dose of enterovirus 71 was able to effi ...201323644889
the development and application of the two real-time rt-pcr assays to detect the pathogen of hfmd.large-scale hand, foot, and mouth disease (hfmd) outbreaks have frequently occurred in china since 2008, affecting more than one million children and causing several hundred children deaths every year. the pathogens of hfmd are mainly human enteroviruses (hevs). among them, human enterovirus 71 (hev71) and coxsackievirus a16 (cva16) are the most common pathogens of hfmd. however, other hevs could also cause hfmd. to rapidly detect hev71 and cva16, and ensure detection of all hevs causing hfmd, t ...201323637836
structures of the procapsid and mature virion of enterovirus 71 strain 1095.enterovirus 71 (ev71) is an important emerging human pathogen with a global distribution and presents a disease pattern resembling poliomyelitis with seasonal epidemics that include cases of severe neurological complications, such as acute flaccid paralysis. ev71 is a member of the picornaviridae family, which consists of icosahedral, nonenveloped, single-stranded rna viruses. here we report structures derived from x-ray crystallography and cryoelectron microscopy (cryo-em) for the 1095 strain o ...201323637404
structures of enterovirus 71 3c proteinase (strain e2004104-tw-cdc) and its complex with rupintrivir.the crystal structure of 3c proteinase (3c(pro)) from enterovirus 71 (ev71) was determined in space group c2221 to 2.2 å resolution. the fold was similar to that of 3c(pro) from other picornaviruses, but the difference in the β-ribbon reported in a previous structure was not observed. this β-ribbon was folded over the substrate-binding cleft and constituted part of the essential binding sites for interaction with the substrate. the structure of its complex with rupintrivir (ag7088), a peptidomim ...201323633597
hand, foot, and mouth disease caused by coxsackievirus a6, thailand, 2012.in thailand, hand, foot, and mouth disease (hfmd) is usually caused by enterovirus 71 or coxsackievirus a16. to determine the cause of a large outbreak of hfmd in thailand during june-august 2012, we examined patient specimens. coxsackievirus a6 was the causative agent. to improve prevention and control, causes of hfmd should be monitored.201323631943
novel substituted heteroaromatic piperazine and piperidine derivatives as inhibitors of human enterovirus 71 and coxsackievirus a16.a series of substituted heteroaromatic piperazine and piperidine derivatives were found through virtual screening based on the structure of human enterovirus 71 capsid protein vp1. the preliminary biological evaluation revealed that compounds 8e and 9e have potent activity against ev71 and coxsackievirus a16 with low cytotoxicity.201323629759
[association of hla-g 14bp gene polymorphisms and plasma shla-g level with susceptibility to ev71 infection in children].explore the relationship between the hla-g 14bp insertion/deletion polymorphism and the infection of enterovirus 71 (ev71) for children.201223627021
[transmission and prevalence patterns of c4a evolutionary lineage of human enterovirus 71 circulating in mainland of china, 2008-2010].to understand the evolutionary relationship between the c4a evolutionary lineage of human enterovirus 71 (hev71) strains circulating in mainland of china during 2008-2010 and 2008 fuyang strains and study the prevalence and transmission patterns of 2008 fuyang strains.201223627020
inflammatory, vascular, and infectious myelopathies in children.acute nontraumatic myelopathies of childhood include inflammatory, infectious, and vascular etiologies. inflammatory immune-mediated disorders of the spinal cord can be categorized as idiopathic isolated transverse myelitis, neuromyelitis optica, and multiple sclerosis. in recent years, human t-cell lymphotropic virus type 1, west nile virus, enterovirus-71, and lyme disease have been increasingly recognized as infectious etiologies of myelopathy, and poliomyelitis remains an important etiology ...201323622308
hepatic damage caused by coxsackievirus b3 is dependent on age-related tissue tropisms associated with the coxsackievirus-adenovirus receptor.coxsackievirus b (cvb) and enterovirus 71 (ev71) are important causes of severe enteroviral diseases in neonates or young children in taiwan. cvb can cause fulminant hepatitis, myocarditis or meningoencephalitis. this study was designed to explore the role of coxsackievirus-adenovirus receptor (car) in the pathogenesis of cvb3-infected hepatocytes via in vitro and mice studies. cvb3 (cvb3/2630) was isolated from liver tissue of a neonate with fulminant hepatitis. cell lines a549, hela, hep2 and ...201323620416
conformational plasticity of the 2a proteinase from enterovirus 71.the 2a proteinase (2a(pro)) is an enterovirally encoded cysteine protease that plays essential roles in both the processing of viral precursor polyprotein and the hijacking of host cell translation and other processes in the virus life cycle. crystallographic studies of 2a(pro) from enterovirus 71 (ev71) and its interaction with the substrate are reported here. ev71 2a(pro) was comprised of an n-terminal domain of a four-stranded antiparallel β sheet and a c-terminal domain of a six-stranded ant ...201323616646
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
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
emerging viral infections.this review highlights research and development in the field of emerging viral causes of encephalitis over the past year.201323591683
rational design of thermostable vaccines by engineered peptide-induced virus self-biomineralization under physiological conditions.the development of vaccines against infectious diseases represents one of the most important contributions to medical science. however, vaccine-preventable diseases still cause millions of deaths each year due to the thermal instability and poor efficacy of vaccines. using the human enterovirus type 71 vaccine strain as a model, we suggest a combined, rational design approach to improve the thermostability and immunogenicity of live vaccines by self-biomineralization. the biomimetic nucleating p ...201323589862
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 laboratory evaluation of medicinal herbs used in china for the treatment of hand, foot, and mouth disease.enterovirus 71 (ev71) and coxsackievirus a16 (cva16) are the causative agents of hand, foot, and mouth disease (hfmd). during recent epidemics of hfmd in china, medicinal herbals and preparations containing herbal extracts have demonstrated therapeutic efficacy with relative safety profiles. there have been no microbiological studies to validate their usefulness for hfmd. we selected 12 commonly used herbs for hfmd from government recommended guidelines as well as published reports and tested fo ...201323554831
[detection the pathogens and analysis the clinical characteristics in children with hand, foot and mouth disease in shanghai during 2009-2011].to investigate the epidemic characteristics of etiological agents and analyze the clinic differences in children with hand, foot and mouth diseases in shanghai.201223547454
[isolation and sequence analysis on virus of hfmd with encephalitis in yantal city].to learn about the pathogen spectrum and genetic characterization of hfmd with encephalitis in yantai city.201223547453
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
a new factor influencing pathogen detection by molecular assay in children with both mild and severe hand, foot, and mouth disease.this study aimed to find novel information concerning pathogen detection and some probable coinfection factors in hand, foot, and mouth disease (hfmd). in this study, 1104 clinically diagnosed hfmd patients were included. enterovirus 71 (ev71), coxsackievirus a16 (ca16), and 14 different respiratory pathogens were examined from nasopharyngeal swabs using polymerase chain reaction (pcr) or reverse transcriptase pcr (rt-pcr). to evaluate the immune activation in hfmd patients, 8 cytokines and igm ...201323535205
adaptation of enterovirus 71 to adult interferon deficient mice.non-polio enteroviruses, including enterovirus 71 (ev71), have caused severe and fatal cases of hand, foot and mouth disease (hfmd) in the asia-pacific region. the development of a vaccine or antiviral against these pathogens has been hampered by the lack of a reliable small animal model. in this study, a mouse adapted ev71 strain was produced by conducting serial passages through a129 (α/β interferon (ifn) receptor deficient) and ag129 (α/β, γ ifn receptor deficient) mice. a b2 sub genotype of ...201323527208
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
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
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