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[relationship between g6pd deficiency and hand-foot-mouth disease induced by enterovirus 71].to study the influence of glucose-6-phosphate dehydrogenase (g6pd) deficiency on hand-foot-mouth disease (hfmd) induced by enterovirus 71 (ev71) , and possible mechanisms.201324034918
[cloning, expression and activity determination of capsid protein vp1 of enterovirus type 71]. 201324027809
crystal structure of 2a proteinase from hand, foot and mouth disease virus.ev71 is responsible for several epidemics worldwide; however, the effective antiviral drug is unavailable to date. the 2a proteinase (2a(pro)) of ev71 presents a promising drug target due to its multiple roles in virus replication, inhibition of host protein synthesis and evasion of innate immunity. we determined the crystal structure of ev71 2a(pro) at 1.85å resolution, revealing that the proteinase maintains a chymotrypsin-like fold. the active site is composed of the catalytic triads c110a, h ...201323973886
proteomic analysis of extremely severe hand, foot and mouth disease infected by enterovirus 71.to clarify the molecular mechanisms that participate in the severe hand, foot and mouth disease (hfmd) infected by enterovirus 71 and to detect any related protein biomarkers, we performed proteomic analysis of protein extracts from 5 extremely severe hfmd children and 5 healthy children.201323961958
transgenic mouse model for the study of enterovirus 71 neuropathogenesis.enterovirus 71 (ev71) typically causes mild hand-foot-and-mouth disease in children, but it can also cause severe neurological disease. recently, epidemic outbreaks of ev71 with significant mortality have been reported in the asia-pacific region, and ev71 infection has become a serious public health concern worldwide. however, there is little information available concerning ev71 neuropathogenesis, and no vaccines or anti-ev71 drugs have been developed. previous studies of this disease have used ...201323959904
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
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
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
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
[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
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
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
[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
first case of severe enterovirus 71 infection in portugal. 201323838666
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
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
ev71-infected cd14(+) cells modulate the immune activity of t lymphocytes in rhesus monkeys.preliminary studies of the major pathogen enterovirus 71 (ev71), a member of the picornaviridae family, have suggested that ev71 may be a major cause of fatal hand, foot and mouth disease cases. currently, the role of the pathological changes induced by ev71 infection in the immunopathogenic response remains unclear. our study focused on the interaction between this virus and immunocytes and indicated that this virus has the ability to replicate in cd14(+) cells. furthermore, these ev71-infected ...201326038477
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
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
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
implications of age-dependent immune responses to enterovirus 71 infection for disease pathogenesis and vaccine design.epidemics of enterovirus serotype 71 (ev71) infection in asia appear to be increasing in size and severity, and there is increasing concern for pandemic spread. efforts are underway to develop an effective ev71 vaccine. however, the immunologic correlates of protection against ev71 infection are not fully understood, and studies suggest that severe complications may result from a combination of pathological immune responses and direct viral effects. severe disease and death typically occur only ...201326619463
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
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
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
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
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
association of ip-10 gene polymorphism with susceptibility to enterovirus 71 infection.enterovirus 71 (ev71) often causes large outbreaks of diseases among children worldwide and its pathogenesis remains unclear. the aim of the present study was to investigate the association between interferon-inducible protein 10 (ip-10) polymorphism in children with ev71 infection. polymerase chain reaction (pcr) and restriction fragment length polymorphism (rflp) were performed to analyze the gene polymorphisms of ip-10 (-1596c/t) in 58 ev71-infected and 48 control patients. the results showed ...201324648959
[identification and characterization of enterovirus 71 isolated in yunnan province].identification and characterization of eight enterovirus 71 samples isolated from yunnan province.201324579470
molecular epidemiology of enterovirus 71 infection in the central region of taiwan from 2002 to 2012.enterovirus 71 (ev71), a causative agent of hand, foot, and mouth disease can be classified into three genotypes and many subtypes. the objectives of this study were to conduct a molecular epidemiological study of ev71 in the central region of taiwan from 2002-2012 and to test the hypothesis that whether the alternative appearance of different ev71 subtypes in taiwan is due to transmission from neighboring countries or from re-emergence of pre-existing local strains. we selected 174 ev71 isolate ...201324391812
[analysis of pathogen spectrum of encephalitis/meningitis in northwestern area of china].to learn the characteristics of pathogen spectrum of encephalitis /meningitis in northwestern area of china.201324378133
complete genome sequence of a human enterovirus 71 strain isolated in wuhan, china, in 2010.the complete genome sequence of a human enterovirus 71 strain (ev71/wuhan/3018/2010), which was isolated in wuhan in 2010, was amplified by a reverse transcription-pcr method and sequenced. phylogenetic analysis based on the complete genome sequence classified this strain into subgenogroup a.201324371206
identification of a series of compounds with potent antiviral activity for the treatment of enterovirus infections.rhinovirus (genus enterovirus) infections are responsible for many of the severe exacerbations of asthma and chronic obstructive pulmonary disease. other members of the genus can cause life-threatening acute neurological infections. there is currently no antiviral drug approved for the treatment of such infections. we have identified a series of potent, broad-spectrum antiviral compounds that inhibit the replication of the human rhinovirus, coxsackie virus, poliovirus, and enterovirus-71. the me ...201324900715
fluorescent primer-based in vitro transcription system of viral rna-dependent rna polymerases.viral infection is a leading cause of disease and death. although vaccines are the most effective method of controlling viral infections, antiviral drugs are also important. here, we established an in vitro transcription system by using fluorescein isothiocyanate-conjugated primers for rna polymerases of viruses that are important disease-causing human pathogens (influenza, hepatitis c, japanese encephalitis viruses, and enterovirus 71). this technology will allow us to analyze rna polymerase ac ...201323103398
quantification of the dynamics of enterovirus 71 infection by experimental-mathematical investigation.enterovirus 71 (ev71) is the causative agent of hand-foot-and-mouth disease and can trigger neurological disorders. ev71 outbreaks are a major public health concern in asia-pacific countries. by performing experimental-mathematical investigation, we demonstrate here that viral productivity and transmissibility but not viral cytotoxicity are drastically different among ev71 strains and can be associated with their epidemiological backgrounds. this is the first report demonstrating the dynamics of ...201323097444
antigenic analysis of divergent genotypes human enterovirus 71 viruses by a panel of neutralizing monoclonal antibodies: current genotyping of ev71 does not reflect their antigenicity.in recent year, enterovirus 71 (ev71)-associated hand, foot and mouth disease (hfmd) has become an important public health issue in china. ev71 has been classified into genotypes a, b1-b5 and c1-c5. with such genetic diversity, whether the convalescent or recovery antibody responses can cross-protect infections from other genotypes remains a question. understanding of the antigenicity of such diverse genetic ev71 isolates is crucial for the ev71 vaccine development. here, a total of 186 clones a ...201323088887
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
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
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
adoptive transfer of macrophages from adult mice reduces mortality in mice infected with human enterovirus 71.human enterovirus 71 (ev71) causes hand, foot and mouth disease in children under 6 years of age, and the neurological complications of this virus can lead to death. until now, no vaccines or drugs have been available for the clinical control of this epidemic. macrophages can engulf pathogens and mediate a series of host immune responses that play a role in the defence against infectious diseases. using immunohistochemistry, we observed the localizations of virus in muscle tissues of ev71-infect ...201323065110
recombinant vp1 protein expressed in pichia pastoris induces protective immune responses against ev71 in mice.human enterovirus 71 (ev71) is one of the major causative agents of hand, foot and mouth disease and is also associated with serious neurological diseases in children. currently, there are no effective antiviral drugs or vaccines against ev71 infection. vp1, one of the major immunogenic capsid proteins of ev71, is widely considered to be the candidate antigen for an ev71 vaccine. in this study, vp1 of ev71 was expressed as a secretory protein with an n-terminal histidine tag in the methylotrophi ...201323159634
microrna-548 down-regulates host antiviral response via direct targeting of ifn-λ1.interferon (ifn)-mediated pathways are a crucial part of the cellular response against viral infection. type iii ifns, which include ifn-λ1, 2 and 3, mediate antiviral responses similar to type i ifns via a distinct receptor complex. ifn-λ1 is more effective than the other two members. transcription of ifn-λ1 requires activation of irf3/7 and nuclear factor-kappa b (nf-κb), similar to the transcriptional mechanism of type i ifns. using reporter assays, we discovered that viral infection induced ...201323150165
characterization of enterovirus 71 capsids using subunit protein-specific polyclonal antibodies.enterovirus 71 (ev71), a member of the enterovirus genus of the picornaviridae family, is one of the major causative agents of hand-foot-and-mouth disease (hfmd), which is prevalent in the asia-pacific region. in this article, a set of capsid subunit protein-specific antibodies was used to characterize the ev71 structural protein processing and to determine the composition and assembly of ev71 capsids. sds-page and western blot analyses showed that the capsids of a purified ev71 preparation, whi ...201323046991
quinacrine impairs enterovirus 71 rna replication by preventing binding of polypyrimidine-tract binding protein with internal ribosome entry sites.since the 1980s, epidemics of enterovirus 71 (ev71) and other enteroviruses have occurred in asian countries and regions, causing a wide range of human diseases. no effective therapy is available for the treatment of these infections. internal ribosome entry sites (iress) are indispensable for the initiation of translation in enteroviruses. several cellular factors, as well as the ribosome, are recruited to the conserved ires during this process. quinacrine intercalates into the rna architecture ...201323301007
antigenic and genetic diversity of human enterovirus 71 from 2009 to 2012, taiwan.different subgenogroups of enterovirus 71 (ev-71) have caused numerous outbreaks of hand, foot, and mouth disease worldwide, especially in the asia-pacific region. during the development of a vaccine against ev-71, the genetic and antigenic diversities of ev-71 isolates from taiwan were analyzed by phylogenetic analyses and neutralization tests. the results showed that the dominant genogroups had changed twice, from b to c and from c to b, between 2009 and 2012. the subgenogroup b5 (b5b cluster) ...201324348916
impact of endothelial nitric oxide synthase gene polymorphism on severity of enterovirus 71-infection in chinese children.genetic polymorphism g894t on the endothelial nitric oxide synthase (enos) gene has been reported as a susceptibility factor in a number of diseases, but evidence of its effect on enterovirus 71 (ev71) infection is lacking. this study investigated the possible association between this polymorphism (rs1799983) and disease severity in chinese children with ev71 infection.201324140479
frequency of human enterovirus 71 in children under 8 years old with aseptic menengitis in tehran.human enterovirus 71 (hev71) was isolated for the first time from an infant with encephalitis in california in 1969 and then spread through the world. it has emerged as a major cause of a vast variety of diseases such as epidemics of hand, foot and mouth disease (hfmd), aseptic meningitis (am), acute flaccid paralysis, and encephalitis. the aim of this study was to determine the prevalence of enterovirus 71 in children < 8 years old who were hospitalized due to primary diagnosis of am in tehran.201324133924
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
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
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