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the preferential infection of astrocytes by enterovirus 71 plays a key role in the viral neurogenic pathogenesis.the pathological manifestations of fatal cases of human hand, foot, and mouth disease (hfmd) caused by enterovirus 71 (ev71) are characterized by inflammatory damage to the central nervous system (cns). here, the dynamic distribution of ev71 in the cns and the subsequent pathological characteristics within different regions of neonatal rhesus macaque brain tissue were studied using a chimeric ev71 expressing green fluorescence protein. the results were compared with brain tissue obtained from th ...201628066727
epidemiological and clinical features of enteroviral acute lower respiratory tract infections in hospitalized paediatric patients in a malaysian tertiary center.human enteroviruses (hevs) have been recognized to cause a significant number of respiratory tract infections in many regions. previous studies conducted to analyse enteroviral respiratory tract infections focused on outbreaks. data in the southeast asian region is still rather limited to date.201628064293
ev71 3d protein binds with nlrp3 and enhances the assembly of inflammasome complex.activation of nlrp3 inflammasome is important for effective host defense against invading pathogen. together with apoptosis-associated speck-like protein containing card domain (asc), nlrp3 induces the cleavage of caspase-1 to facilitate the maturation of interleukin-1beta (il-1β), an important pro-inflammatory cytokine. il-1β subsequently plays critical roles in inflammatory responses by activating immune cells and inducing many secondary pro-inflammatory cytokines. although the role of nlrp3 i ...201728060938
evaluation of antiviral activity of zanthoxylum species against picornaviruses.human rhinoviruses and enteroviruses (family picornaviridae) infect millions of people worldwide each year, but little is known about effective therapeutical treatment for the infection caused by these viruses. we sought to determine whether or not zanthoxylum (rutaceae) species can exhibit antiviral activity against picornaviruses. the leaf parts of four zanthoxylum species were extracted with methanol, and the extracts were investigated for their antiviral activity against picornaviruses using ...201628053847
epidemiologic features of enterovirus 71-associated hand-foot-and-mouth disease from 2009 to 2013 in zhejiang, china.enterovirus 71 (ev71) usually causes hand-foot-and-mouth disease (hfmd) with severe clinical symptoms and even deaths in china. there is no efficient antiviral drug to protect against severe ev71-associated hfmd, making the development of ev71 vaccines therefore a priority. however, the potential target subject population(s) to be immunized with ev71 vaccine are not well understood. in this study, we characterized the epidemiology regarding ev71-associated hfmd on the basis of provincial-level s ...201628042848
changes of circulating th22 cells in children with hand, foot, and mouth disease caused by enterovirus 71 infection.interleukin (il)-22+cd4+t (th22) cells play crucial roles in the pathogenesis of autoimmune diseases and infectious diseases, although the role of th22 cells remains largely unclear in children with hand, foot, and mouth disease (hfmd) caused by enterovirus 71 (ev71). this study aims to explore the role of circulating il-22+il-17a-cd4+t (cth22) cells in children with ev71-associated hfmd. we found that during the acute stage of illness, the frequencies of cth22 and circulating il-22+il-17a+cd4+t ...201628030850
structure-activity relationship studies on a trp dendrimer with dual activities against hiv and enterovirus a71. modifications on the amino acid.we have recently described a new class of dendrimers with tryptophan (trp) on the surface that show dual antiviral activities against hiv and ev71 enterovirus. the prototype compound of this family is a pentaerythritol derivative with 12 trps on the periphery. here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. with this aim, novel dendrimers containing different amino acids (aromatic and non-a ...201728017762
galectin-3 and its genetic variation rs4644 modulate enterovirus 71 infection.galectin-3, a chimeric type β-galactoside-binding protein, is known to modulate viral infection; however, its role in enterovirus 71 (ev71) infection has not been investigated. we generated galectin-3 null rhabdomyosarcoma (rd) cells and evaluated whether ev71 infection would be affected. in galectin-3 null cells, the released and intracellular ev71 viral loads were suppressed after 24 h of infection, and cell death rates were significantly lower, while cell proliferation remained unaltered. in ...201628002441
[surveillance on the epidemiological and etiological characteristics of hand-foot-mouth disease during the outbreaks in three cities of jiangsu province, 2012-2015].objective: to analyze the epidemiological and etiological characteristics through monitoring the outbreaks of hand-foot-mouth disease (hfmd), in three cities of jiangsu province from 2012 to 2015 and to provide evidence for prevention and control of the disease. methods: data related to cases of hfmd during the outbreaks was collected through active surveillance programs in three cities of jiangsu province, under the guidelines of clusters and outbreaks of hfmd (2012 edition hfmd). features rela ...201627998408
characterization of enterovirus 71 infection and associated outbreak of hand, foot, and mouth disease in shawo of china in 2012.infection of enterovirus 71 (ev71) and associated hand, foot, and mouth disease (hfmd) are recognized as emerging public health issues worldwide. hundreds of thousands of children are annually infected with ev71 and develop hfmd in china alone. studies of ev71 infection are critical to the treatment and prevention of the associated hfmd outbreaks. in this report, we studied an outbreak of 105 hfmd cases in shawo township of china between september to october 2012. more than 90% of cases were chi ...201627941929
an elaborate landscape of the human antibody repertoire against enterovirus 71 infection is revealed by phage display screening and deep sequencing.enterovirus 71 (ev71) causes outbreaks of hand, foot and mouth disease (hfmd), primarily in the asia-pacific area, that are often associated with complications of severe to fatal neurological symptoms. there are currently no anti-viral therapies or vaccines available for the treatment of ev71 infection. illustrating human antibody responses neutralizing ev71 infection could potentially provide valuable information for the development of effective therapies and vaccines. here, we constructed a co ...201727929745
comparative genomic analysis of enterovirus 71 revealed six new potential neurovirulence-associated sites.in the present study, the complete genomes of four common (4/ev71/wenzhou/chn/2014, 15/ ev71/wenzhou/chn/2014, 116/ev71/wenzhou/ chn/2014, and 120/ev71/wenzhou/chn/2014) and two virulent (11/ev71/wenzhou/chn/2014 and 109/ev71/wenzhou/chn/2014) enterovirus 71 (ev71) isolates were sequenced and described. they are 7405 bp in length and belong to ev71 sub-genotype c4 (c4a cluster). nucleotide sequence alignment revealed six nucleotide variations (gp151→tp151, gp199→ap199, gp261→tp261, ap328→cp328, ...201627927278
severe paediatric conditions linked with ev-a71 and ev-d68, france, may to october 2016.we report 59 cases of severe paediatric conditions linked with enterovirus (ev)-a71 and ev-d68 in france between may and october 2016. fifty-two children had severe neurological symptoms. ev sequence-based typing for 42 cases revealed ev-a71 in 21 (18 subgenotype c1, detected for the first time in france) and ev-d68 in eight. clinicians should be encouraged to obtain stool and respiratory specimens from patients presenting with severe neurological disorders for ev detection and characterisation.201627918268
motor coordination and balance measurements reveal differential pathogenicity of currently spreading enterovirus 71 strains in human scarb2 transgenic mice.enterovirus 71 (ev71) has caused large-scale epidemics with neurological complications in the asia-pacific region. the c4a and b5 strains are the two major genotypes circulating in many countries recently. this study used a new protocol, a motor coordination task, to assess the differential pathogenicity of c4a and b5 strains in human scarb2 transgenic mice. we found that the pathogenicity of c4a viruses was more severe than that of b5 viruses. moreover, we discovered that an increased level of ...201627902385
hand, foot, and mouth disease in hunan province, china, 2009-2014: epidemiology and death risk factors.hand, foot, and mouth disease (hfmd) is an arising public health problem in asia, including china. epidemiological data is necessary to enable judicious public health responses and interventions. we analyzed the epidemiological and laboratory data of 759,301 hfmd cases reported to the hunan provincial center for disease control and prevention from 1 january 2009 to 31 december 2014. univariate and multivariable conditional logistic regression analyses were used to identify risk factors of fatali ...201627898715
identification of molecular determinants of cell culture growth characteristics of enterovirus 71.hand, foot and mouth disease is caused by enterovirus 71 (ev-a71) and coxsackieviruses. ev-a71 infection is associated with high fever, rashes and ulcers but more severe symptoms such as cardiopulmonary failure and death have been reported. the lack of vaccines highlighted the urgency of developing preventive agents against ev-a71. the molecular determinants of virulent phenotypes of ev-a71 is unclear. it remains to be investigated if specific molecular determinants would affect the cell culture ...201627894305
inhibitory effects of bee venom and its components against viruses in vitro and in vivo.bee venom (bv) from honey bee (apis melifera l.) contains at least 18 pharmacologically active components including melittin (mlt), phospholipase a2 (pla2), and apamin etc. bv is safe for human treatments dose dependently and proven to possess different healing properties including antibacterial and antiparasitidal properties. nevertheless, antiviral properties of bv have not well investigated. hence, we identified the potential antiviral properties of bv and its component against a broad panel ...201627888461
vp1 residues around the five-fold axis of enterovirus a71 mediate heparan sulfate interaction.enterovirus a71 (ev-a71) is a neurotropic enterovirus that uses heparan sulfate as an attachment receptor. the molecular determinants of ev-a71-heparan sulfate interaction are unknown. with in silico heparin docking and mutagenesis of all possible lysine residues in vp1, we identified that k162, k242 and k244 are responsible for heparin interaction and inhibition. ev-a71 mutants with k242a and k244a rapidly acquired compensatory mutations, t100k or e98a, and q145r-t237n respectively, which resto ...201727875780
sirt1 inhibits ev71 genome replication and rna translation by interfering with the viral polymerase and 5'utr rna.enterovirus 71 (ev71) possesses a single-stranded positive rna genome that contains a single open reading frame (orf) flanked by a 5' untranslated region (5'utr) and a polyadenylated 3'utr. here, we demonstrated that ev71 activates the production of silent mating type information regulation 2 homolog 1 (sirt1), a histone deacetylase (hdac). ev71 further stimulates sirt1 sumoylation and deacetylase activity, and enhances sirt1 translocation from the nucleus to the cytoplasm. more interestingly, a ...201627875274
development of a fluorescence resonance energy transfer-based intracellular assay to identify novel enterovirus 71 antivirals.enterovirus 71 (ev71) is considered one of the most virulent pathogens in the family picornaviridae. however, there have been no effective treatments for the severe complications caused by ev71. development of new drugs against targets that are essential for viral replication often requires screening large collections of compounds, for which a high-throughput screening platform is needed. in this study, a drug-screening platform was developed based on a genetically engineered cell line that disp ...201727873071
immunoreactivity analysis of the nonstructural proteins of human enterovirus 71.human enterovirus 71 (ev-a71) is one of the main etiological agents of hand, foot, and mouth disease (hfmd), which has been prevalent mainly in the asia-pacific region in the past several decades. the nonstructural proteins of ev-a71 will be expressed significantly during viral replication in host cells after ev-a71 infection. for the determination of the antibodies response against nonstructural proteins of ev-a71, in this study, the complete 2abc, 3abc, and 3d proteins were expressed in escher ...201727870604
clinically isolated enterovirus a71 subgenogroup c4 strain with lethal pathogenicity in 14-day-old mice and the application as an ev-a71 mouse infection model.the enterovirus a71 (ev-a71) subgenogroup c4 is prevalent in china. ev-a71 causes hand, foot and mouth disease (hfmd) in children and may lead to severe neurological diseases. the development of antiviral and protective vaccines against ev-a71 is significantly hindered by the lack of suitable animal models to recapitulate human neurological symptoms. in this study, gz-cii, a highly virulent ev-a71 subgenogroup c4 strain, was isolated from hospitalized children with hfmd. intraperitoneal infectio ...201727864074
enterovirus 71 infection of motor neuron-like nsc-34 cells undergoes a non-lytic exit pathway.enterovirus 71 (ev71) causing hand, foot and mouth disease, is regarded as the most important neurotropic virus worldwide. ev71 is believed to replicate in muscles and infect motor neurons to reach the central nervous system (cns). to further investigate the mechanisms involved, we have employed the motor neuron cell line nsc-34. nsc-34 cells were permissive to ev71 and virus production yields were strain-dependent with differential efficacy at the entry, replication and egress steps. furthermor ...201627849036
glucocorticoids prevent enterovirus 71 capsid protein vp1 induced calreticulin surface exposure by alleviating neuronal er stress.severe hand-foot-and-mouth disease (hfmd) caused by enterovirus 71 (ev71) always accompanies with inflammation and neuronal damage in the central nervous system (cns). during neuronal injuries, cell surface-exposed calreticulin (ecto-crt) is an important mediator for primary phagocytosis of viable neurons by microglia. our data confirmed that brainstem neurons underwent neuronophagia by glia in ev71-induced death cases of hfmd. ev71 capsid proteins vp1, vp2, vp3, or vp4 did not induce apoptosis ...201727848175
enterovirus 71 3c promotes apoptosis through cleavage of pinx1, a telomere binding protein.enterovirus 71 (ev71) is an emerging pathogen causing hand, foot, and mouth disease (hfmd) and fatal neurological diseases in infants and young children due to their underdeveloped immunocompetence. ev71 infection can induce cellular apoptosis through a variety of pathways, which promotes ev71 release. the viral protease 3c plays an important role in ev71-induced apoptosis. however, the molecular mechanism responsible for 3c-triggered apoptosis remains elusive. here, we found that ev71 3c direct ...201727847364
rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment.human enterovirus 71 (ev71) is the primary causative agent of recent large-scale outbreaks of hand, foot, and mouth disease (hfmd) in asia. currently, there are no drugs available for the prevention and treatment of hfmd. in this study, we compared the anti-ev71 activities of three natural compounds, rheum emodin, artemisinin and astragaloside extracted from chinese herbs chinese rhubarb, artemisia carvifolia and astragalus, respectively, which have been traditionally used for the treatment and ...201727840410
enterovirus-71 genotype c isolated in peru between 2006 and 2009.enterovirus-71 (ev71) was first isolated in california, united states in 1969, belongs to the genus enterovirus, family picornaviridae. although infection normally causes mild, often undiagnosed illness, it can cause central nervous system infections that could turn fatal. based on vp1 gene analysis, ev71 has been classified into six separate genotypes. although the molecular epidemiology of ev71 has been well described via studies originating from asia and europe, it is mostly unknown in south ...201627833060
enterovirus 71 infection and neurological complications.since the outbreak of the enterovirus 71 (ev71) infection in malaysia in 1997, large epidemics of ev71 have occurred in the asia-pacific region. many children and infants have died from serious neurological complications during these epidemics, and ev71 infection has become a serious public health problem in these areas. ev71 infection causes hand, foot and mouth disease (hfmd) in children, and usually resolves spontaneously. however, ev71 occasionally involves the central nervous system (cns), ...201627826325
children's caregivers and public playgrounds: potential reservoirs of infection of hand-foot-and-mouth disease.hand-foot-and-mouth disease (hfmd) is a common infectious disease, which has led to millions of clinical cases and hundreds of deaths every year in china. this study aimed to exploring the effects on hfmd transmission of children's caregivers and public area, as well as trying to locate the potential reservoirs of infections in primary cases. total children's 257 samples (98 children's caregivers and 159 environmental samples) were tested for the presence of universal enterovirus, enterovirus 71 ...201627819276
n-terminal pro-b-type natriuretic peptide for the prognostic prediction of severe enterovirus 71-associated hand, foot, and mouth disease.the aim of this study was to determine whether n-terminal pro-b-type natriuretic peptide (nt-probnp) can predict impending brainstem encephalitis, pulmonary edema, pulmonary hemorrhage, cardiopulmonary failure, and death in children with severe enterovirus 71 (ev71)-associated hand, foot, and mouth disease (hfmd).201727818360
[expression of vasoactive intestinal peptide in peripheral blood of children with hand, foot and mouth disease].to investigate the expression of vasoactive intestinal peptide (vip) in peripheral blood of children with hand, foot and mouth disease and its significance.201627817774
sequence analysis of the first c2 subgenogroup strain of enterovirus 71 isolated in korea.enterovirus 71 (ev71) is an important causative agent of hand-foot-and-mouth disease with severe neurological complications, which may lead to death in children. large outbreaks caused by ev71 have frequently occurred in asia-pacific region.201627816018
transcutaneous immunization via rapidly dissolvable microneedles protects against hand-foot-and-mouth disease caused by enterovirus 71.recent large outbreaks of hand-foot-and-mouth disease (hfmd) have seriously affected the health of young children. enterovirus 71 (ev71) is the main causative agent of hfmd. herein, for the first time, rapidly dissolvable microneedles (mns) loaded with ev71 virus-like particles (vlps) were evaluated whether they could induce robust immune responses that confer protection against ev71 infection. the characteristics of prepared mns including hygroscopy, mechanical strength, insertion capacity, dis ...201627793685
maternal environmental risk factors for congenital hydrocephalus: a systematic review.objective congenital hydrocephalus (ch) is one of the most frequent cns congenital malformations, representing an entity with serious pathological consequences. although several studies have previously assessed child-related risk factors associated with ch development, there is a gap of knowledge on maternal environmental risk factors related to ch. the authors have systematically assessed extrinsic factors in the maternal environment that potentially confer an increased risk of ch development. ...201627798989
new findings, classification and long-term follow-up study based on mri characterization of brainstem encephalitis induced by enterovirus 71.to report the diversity of mri features of brainstem encephalitis (be) induced by enterovirus 71. this is supported by implementation and testing of our new classification scheme in order to improve the diagnostic level on this specific disease.201627798639
enterovirus 71 inhibits cellular type i interferon signaling by inhibiting host rig-i ubiquitination.enterovirus 71 (ev71) is a human pathogen that induces hand, foot, and mouth disease (hfmd) and fatal neurological diseases in young children and infants. pathogenicity of ev71 is likely related to its ability to evade host innate immunity through inhibiting cellular type i interferon signaling. however, it is less well understood the molecular events governing this process. in this study, we found that ev71 infection suppressed the induction of antiviral immunity by inhibiting the expression le ...201627633794
a severe pediatric infection with a novel enterovirus a71 strain, thuringia, germany.infection by enterovirus a71 (ev-a71) is an important cause of hand, foot, and mouth disease (hfmd). outbreaks including severe cases with neurological and cardiopulmonary complications have been reported particularly from southeast asia. in europe, the epidemiology of ev-a71 is not well understood. in summer 2015, a two-year-old girl from thuringia, germany, presented with rhombencephalitis/brainstem encephalitis associated with severe neurological and cardiopulmonary complications. ev-a71 was ...201627771495
gene sequencing and variable site analyzing of coding region of two enterovirus a71 isolates with different clinical phenotypes.currently, it is still controversial that if the pathogenicity of ev-a71 causing severe or mild hand, foot, and mouth disease (hfmd) is associated with viral nucleotide or amino acid sequence(s). in this study, 19 clinical strains were detected in samples from diagnosed patients of ev-a71-caused hfmd with mild or severe symptoms. then, vp1-2a fragment sequences of 19 ev-a71 isolates were determined, the phylogenetic analysis, based on vp1 sequences of 19 ev-a71 stains in this study and which of ...201627566335
epidemiological features of hand, foot and mouth disease during the period of 2008-14 in wenzhou, china.this study aimed to analyze the epidemiological characteristics of hand, foot and mouth disease (hfmd) during 2008-14 in wenzhou, china. the epidemiological data of hfmd retrieved from the wenzhou center for disease control and prevention were retrospectively analyzed. hfmd infections with enterovirus 71 (ev71), cox a16 or other pathogens were further verified by polymerase chain reaction (pcr) and real-time pcr. a total of 213 617 cases of hfmd were reported between 2008 and 2014 in wenzhou. th ...201627765889
n-terminal pro-brain natriuretic peptide levels associated with severe hand, foot and mouth disease.severe hand, foot, and mouth disease (hfmd) is sometimes associated with serious complications such as acute heart failure that can cause substantial child mortality. n-terminal pro-brain natriuretic peptide (nt-probnp) is a sensitive and specific biomarker of congestive heart failure. the aim of this study was to use plasma nt-probnp levels to establish the severity of childhood hfmd.201627760526
enterovirus 71 meningoencephalitis with extensive white matter damage. 201627753776
enzyme-free colorimetric determination of ev71 virus using a 3d-mno2-peg nanoflower and 4-mba-ma-agnps.we present a simple colorimetric assay for ev71 virus detection based on the aggregation of 4-mercaptobenzoic acid (4-mba) and melamine (ma) modified silver nanoparticles (4-mba-ma-agnps) in the presence of mn(2+). the ev71-ab1 was incubated on a 96-well plate and the ev71-ab2 was labeled on the surface of three-dimensional nanoflower-like mno2-peg (3d-mno2-peg). after layer-by-layer immunoreactions, the ev71 virus and the corresponding 3d-mno2-peg-ab2 were captured on the plate. with the additi ...201627714132
epidemiological and genetic analysis of hand-foot-mouth disease by enterovirus a71 in taizhou, p. r. china, between 2010 and 2013.out of a population of 1,098 enteroviruses (evs)-positive hand, foot, and mouth disease (hfmd) specimens, 352 were screened positive for ev-a71-accounting for 32.1% of all ev-positive specimens. this percentage denotes ev-a71 as the second major serotype of enteroviruse among hfmd suffers in taizhou. an epidemic outbreak of ev-a71 among hfmd children was found in taizhou in the second quarter of 2012. phylogeny analysis based on the vp1 complete sequences leads us to find a sub-clade (designated ...201727671219
mov10 interacts with enterovirus 71 genomic 5'utr and modulates viral replication.as a cytoplasmic parasite, rna virus develops sophisticated mechanisms to counter host defense and utilize host proteins to facilitate its replication. here we found moloney leukemia virus 10 (mov10), a highly conserved cellular protein belonging to sf1 helicase family, played critical roles in ev71 infection. silencing cellular mov10 could restrict ev71 replication, while over-expressing mov10 resulted in increased viral replication at low dosage and repressed viral replication at high dosage. ...201627666477
molecular epidemiology of human enterovirus 71 at the origin of an epidemic of fatal hand, foot and mouth disease cases in cambodia.human enterovirus 71 (ev-a71) causes hand, foot and mouth disease (hfmd). ev-a71 circulates in many countries and has caused large epidemics, especially in the asia-pacific region, since 1997. in april 2012, an undiagnosed fatal disease with neurological involvement and respiratory distress occurred in young children admitted to the kantha bopha children's hospital in phnom penh, cambodia. most died within a day of hospital admission, causing public panic and international concern. in this study ...201627651091
antiviral activities of peptide-based covalent inhibitors of the enterovirus 71 3c protease.hand, foot and mouth disease is a highly contagious disease caused by a range of human enteroviruses. outbreaks occur regularly, especially in the asia-pacific region, putting a burden on public healthcare systems. currently, there is no antiviral for treating this infectious disease and the only vaccines are limited to circulation in china, presenting an unmet medical need that needs to be filled urgently. the human enterovirus 3 c protease has been deemed a plausible drug target due to its ess ...201627645381
preparation of quaternary amine monolithic column for strong anion-exchange chromatography and its application to the separation of enterovirus 71.large size virion is unable to diffuse into pores of conventional porous chromatography particles. therefore, separation of virion by conventional column-packing materials is not quite efficient. to solve this problem, a monolithic column with large convective pores and quaternary amine groups was prepared and was applied to separate enterovirus 71 (ev71, ≈5700-6000kda). cross-section, pore structure, hydrodynamic performance, adsorption property and dynamic binding capacity of prepared monolith ...201627643575
sumo modification stabilizes enterovirus 71 polymerase 3d to facilitate viral replication.accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. ubiquitination and sumoylation are extensively studied posttranslational modifications (ptms) that play critical roles in diverse biological processes. cross talk between ubiquitination and sumoylation of both host and viral proteins has been reported to result in distinct functional consequences. enterovirus 71 (ev71), an rna virus belonging to the family picornaviridae, is a common cause ...201627630238
methylcrotonoyl-coa carboxylase 1 potentiates rlr-induced nf-κb signaling by targeting mavs complex.rna virus infections are detected by the rig-i family of receptors, which signal through the adaptor molecule mitochondrial antiviral signaling (mavs). mavs then recruits the adaptor's tumor necrosis factor receptor-associated factor (traf) 3 and traf6, which in turn activate irf3 and nf-κb, respectively, to induce interferons (ifns) and inflammatory responses. here we show that the biotin-containing enzyme methylcrotonoyl-coa carboxylase 1 (mccc1) enhances virus-induced, mavs-mediated ifn and i ...201627629939
single dose of an adenovirus vectored mouse interferon-α protects mice from lethal ev71 challenge.enterovirus 71 (ev71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. interferon (ifn) can inhibit the replication of many viruses with low cytotoxic effects. previously, an adenovirus vectored mouse interferon-α (def201), subtype 5, was generated by wu et al, 2007. in this study, the antiviral effects of def201 against ev71 were evaluated in a murine model. 6-day-old balb/c mice were administered a single dose of def201 before or after infection with ...201627623347
quantitative proteomic analysis of escherichia coli heat-labile toxin b subunit (ltb) with enterovirus 71 (ev71) subunit vp1.the nontoxic heat-labile toxin (lt) b subunit (ltb) was used as mucosal adjuvant experimentally. however, the mechanism of ltb adjuvant was still unclear. the ltb and enterovirus 71 (ev71) vp1 subunit (evp1) were constructed in pet32 and expressed in e. coli bl21, respectively. the immunogenicity of purified evp1 and the adjuvanticity of ltb were evaluated via intranasal immunization evp1 plus ltb in balb/c mice. in order to elucidate the proteome change triggered by the adjuvant of ltb, the pro ...201627618897
the current status of the disease caused by enterovirus 71 infections: epidemiology, pathogenesis, molecular epidemiology, and vaccine development.enterovirus 71 (ev71) infections have a major public health impact in the asia-pacific region. we reviewed the epidemiology, pathogenesis, and molecular epidemiology of ev71 infection as well as ev71 vaccine development. previous studies were found using the search terms "enterovirus 71" and "epidemiology" or "pathogenesis" or "molecular epidemiology" or "vaccine" in medline and pubmed. articles that were not published in the english language, manuscripts without an abstract, and opinion article ...201627618078
structure-activity relationship study of peptidomimetic aldehydes as enterovirus 71 3c protease inhibitors.a series of peptidomimetic aldehydes were designed, synthesized, and evaluated for their biochemical activity against 3c protease (3c(pro)) and anti-enterovirus 71 (ev71) activity in vitro. molecular docking revealed that 5s (ic50 = 0.22 ± 0.07 μm, ec50 = 0.18 ± 0.05 μm) could bind well to the active site of ev71 3c(pro), which was consistent with the biological data compared to reference 5a (ic50 = 0.54 ± 0.02 μm, ec50 = 0.26 ± 0.07 μm). structure and relationship study led to the discovery of ...201627614190
efficacy of high-dose methylprednisolone pulse therapy in the treatment of enterovirus 71 encephalitis.to investigate the efficacy of high-dose methylprednisolone pulse therapy in the treatment of enterovirus 71 (ev71) encephalitis. to determine whether high-dose methylprednisolone pulse therapy should be used, 80 cases of pediatric patients with ev71 encephalitis were randomly divided into steroid pulse therapy group and non-steroid pulse therapy group and their clinical information was compared using statistic analysis. there was no statistical difference in the duration of fever, duration of n ...201627592493
enterovirus 71 2b induces cell apoptosis by directly inducing the conformational activation of the proapoptotic protein bax.to survive and replicate within a host, many viruses have evolved strategies that target crucial components within the apoptotic cascade, leading to either inhibition or induction of cell apoptosis. enterovirus 71 (ev71) infections have been demonstrated to impact the mitochondrial apoptotic pathway and induce apoptosis in many cell lines. however, the detailed mechanism of ev71-induced apoptosis remains to be elucidated. in this study, we report that ev71 2b protein (2b) localized to the mitoch ...201627558414
epidemiology and virologic investigation of human enterovirus 71 infection in the republic of korea from 2007 to 2012: a nationwide cross-sectional study.enterovirus (ev) 71 is the main pathogen associated with hand, foot and mouth disease (hfmd) or herpangina. outbreaks of hfmd caused by ev71 infection are associated severe neurological disease and high mortality rates in children. several sporadic cases of ev71 infection occurred in the republic of korea (rok) in 2000, and ev71 infections were not reported thereafter until 2006. in this prospective study, we report the epidemic and virologic characteristics of the ev71 endemic from 2007 to 2012 ...201627538397
human igg fc promotes expression, secretion and immunogenicity of enterovirus 71 vp1 protein.enterovirus (ev71) can cause severe neurological diseases, but the underlying pathogenesis remains unclear. the capsid protein, viral protein 1 (vp1), plays a critical role in the pathogenicity of ev71. high level expression and secretion of vp1 protein are necessary for structure, function and immunogenicity in its natural conformation. in our previous studies, 5 codon-optimized vp1 dna vaccines, including wt-vp1, tpa-vp1, vp1-d, vp1-hfc and vp1-mfc, were constructed and analyzed. they expresse ...201627533931
prediction of protection against asian enterovirus 71 outbreak strains by cross-neutralizing capacity of serum from dutch donors, the netherlands.outbreaks of human enterovirus 71 (ev-71) in asia are related to high illness and death rates among children. to gain insight into the potential threat for the population of europe, we determined the neutralizing activity in intravenous immunoglobulin (ivig) batches and individual serum samples from donors in the netherlands against ev-71 strains isolated in europe and in asia. all ivig batches and 41%, 79%, and 65% of serum samples from children ≤5 years of age, women of childbearing age, and h ...201627533024
development of novel mirna-based vaccines and antivirals against enterovirus 71.the hand, foot and mouth disease (hfmd) is caused by enterovirus 71 (ev-a71) and coxsackieviruses. common hfmd symptoms are high fever (≥ 39°c), rashes, and ulcers but complications due to virulent ev-a71 may arise leading to cardiopulmonary failure and death. the lack of vaccines and antiviral drugs against ev-a71 highlights the urgency of developing preventive and treatment agents. recent studies have reported the emergence of novel antiviral agents and vaccines that utilize micrornas (mirnas) ...201627510488
a new animal model containing human scarb2 and lacking stat-1 is highly susceptible to ev71.enterovirus 71 (ev71) is a major threat to children worldwide. children infected with ev71 could develop subclinical infection and hand-foot-and -mouth disease (hfmd). in severe cases, patients could develop encephalitis, paralysis, pulmonary edema, and death. a more user-friendly and robust animal model is essential to investigating ev71 pathogenesis. here, we established a hybrid (hscarb2(+/+)/stat-1(-/-)) mouse strain from crossbreeding scarb2 transgenic and stat-1 ko mice, and compared the s ...201627499235
molecular evolution and the global reemergence of enterovirus d68 by genome-wide analysis.human enterovirus d68 (ev-d68) was first reported in the united states in 1962; thereafter, a few cases were reported from 1970 to 2005, but 2 outbreaks occurred in the philippines (2008) and the united states (2014). however, little is known regarding the molecular evolution of this globally reemerging virus due to a lack of whole-genome sequences and analyses. here, all publically available sequences including 147 full and 1248 partial genomes from genbank were collected and compared at the cl ...201627495059
inhibitory effects of an aqueous extract from cortex phellodendri on the growth and replication of broad-spectrum of viruses in vitro and in vivo.cortex phellodendri (c. phellodendri), the dried trunk bark of phellodendron amurense ruprecht, has been known as a traditional herbal medicine, showing several bioactivities. however, antiviral activity of c. phellodendri aqueous extract (cp) not reported in detail, particularly aiming the prophylactic effectiveness.201627484768
epidemiological features and spatio-temporal clusters of hand-foot-mouth disease at town level in fuyang, anhui province, china (2008-2013).hand-foot-mouth disease (hfmd) is a frequently occurring epidemic and has been an important cause of childhood mortality in china. given the disease's significant impact nationwide, the epidemiological characteristics and spatio-temporal clusters in fuyang from 2008 to 2013 were analysed in this study. the disease exhibits strong seasonality with a rising incidence. of the reported hfmd cases, 63·7% were male and 95·2% were preschool children living at home. the onset of hfmd is age-dependent an ...201627477953
a cluster of enterovirus 71 subgenogroup c2 in a nursery school, italy, 2014.during october 2014, enterovirus (ev) rna was detected in the stools of four children attending the same class in a nursery school, and hospitalized with mild febrile and vomiting disease in parma, italy. upon sequencing, the viruses were characterized as ev71 subgenogroup c2. phylogenetic analysis of the four ev71 c2 viruses allowed the distinction of a diverging lineage within subgenogroup c2, containing the italian ev71 c2 strains and viruses detected in france in 2013. the identification of ...201627455182
a single mutation in the vp1 of enterovirus 71 is responsible for increased virulence and neurotropism in adult interferon-deficient mice.hand, foot, and mouth disease (hfmd) has spread throughout the asia-pacific region, affecting millions of young children, who develop symptoms ranging from painful blisters around their mouths and hands to neurological complications. many members of the genus enterovirus (family picornaviridae) cause hfmd. enterovirus 71 (ev71) is one of the primary causative agents and has been linked to severe disease. vaccine efficacy and pathogenesis studies for ev71 have been limited because there is a lack ...201627440896
increased seroprevalence of enterovirus 71 ige antibodies in asthmatic compared with non-asthmatic children.asthma is a common pediatric chronic inflammatory airway disease. respiratory viral infections are frequent infectious triggers for exacerbations of asthma.201627440276
recombinant enterovirus a71 subgenogroup c1 strains, germany, 2015. 201627439117
towards public health surveillance of intensive care services in nsw, australia.outbreaks of known and novel pathogens causing very severe illness increase the risk to public health in a globalised community and alarm the public. intensive care units (icus) may be an underused setting for public health surveillance. this study investigates the electronic record for intensive care (eric), an electronic clinical information and management system being developed for new south wales icus, and its surveillance opportunity offerings.201627421345
quinone/hydroquinone meroterpenoids with antitubercular and cytotoxic activities produced by the sponge-derived fungus gliomastix sp. zsds1-f7.fifteen compounds, including six quinone/hydroquinone meroterpenoids, purpurogemutantin (1), macrophorin a (2), 4'-oxomacrophorin (3), 7-deacetoxyyanuthone a (4), 2,3-hydro-deacetoxyyanuthone a (5), 22-deacetylyanuthone a (6), anicequol (7), three roquefortine derivatives, roquefortine c (8), (16s)-hydroxyroquefortine c (9), (16r)-hydroxyroquefortine c (10), dihydroresorcylide (11), nectriapyrone (12), together with three fatty acid derivatives, methyl linoleate (13), phospholipase a2 (14), meth ...201727417331
[preparation of monoclonal antibodies against enterovirus type 71 with an epitope-incorporated adenovirus type 3 vector].objective to develop the monoclonal antibodies (mabs) against enterovirus type 71 (ev71). methods two neutralization epitopes, sp70 and sp55, from ev71 were cloned into the hexon gene of adenovirus type 3 to generate a recombinant adenovirus type 3 (r1r2a3) presenting sp70 and sp55 antigens. balb/c mice were immunized with the r1r2a3. the mabs were developed with hybridoma technology and were analyzed with microneutralizing assay, indirect elisa, western blotting and direct immunofluorescence as ...201627412945
interleukin-27 as a novel biomarker for early cardiopulmonary failure in enterovirus 71-infected children with central nervous system involvement.enterovirus 71 (ev71) is a major pathogen for severe hand, foot, and mouth disease (hfmd), which leads to severe neurological complications and has high morbidity and mortality. reliable biomarker for the prediction of deterioration in ev71-infected children with central nervous system (cns) involvement may reduce the cardiopulmonary failure and mortality. here, we found that serum il-27 levels were significantly higher in stage iii ev71-infected hfmd patients with early cardiopulmonary failure ...201627403033
development of a full-length cdna-derived enterovirus a71 vaccine candidate using reverse genetics technology.enterovirus a71 (ev-a71) is responsible for epidemics of hand, foot and mouth disease (hfmd) in young children. to circumvent difficulties in obtaining clinical enterovirus isolates that might be contaminated with other viruses, a platform technology was developed to quickly generate vaccine virus strains based on the published enterovirus genomic sequences. a recombinant plasmid containing the full-length infectious cdna clone of ev-a71 vaccine strain e59 was directly generated after transfecti ...201627387826
time series modeling of pathogen-specific disease probabilities with subsampled data.many diseases arise due to exposure to one of multiple possible pathogens. we consider the situation in which disease counts are available over time from a study region, along with a measure of clinical disease severity, for example, mild or severe. in addition, we suppose a subset of the cases are lab tested in order to determine the pathogen responsible for disease. in such a context, we focus interest on modeling the probabilities of disease incidence given pathogen type. the time course of t ...201727378138
vesicular stomatitis virus-based vaccines expressing ev71 virus-like particles elicit strong immune responses and protect newborn mice from lethal challenges.enterovirus 71 (ev71) belonging to the picornaviridae family is considered the most frequently detected causative agent in hand-foot-and-mouth disease (hfmd) and is a serious threat to public health in the asia-pacific region. there are currently no approved vaccines or effective drugs for ev71. in this study, using recombinant vesicular stomatitis virus (rvsv) expressing viral vp1 protein (mvp1) of ev71 as a control, we generated two types of rvsvs that can form ev71 virus-like particles (vlps) ...201627373596
analysis of the synonymous codon usage bias in recently emerged enterovirus d68 strains.understanding the codon usage pattern of a pathogen and relationship between pathogen and host's codon usage patterns has fundamental and applied interests. enterovirus d68 (ev-d68) is an emerging pathogen with a potentially high public health significance. in the present study, the synonymous codon usage bias of 27 recently emerged, and historical ev-d68 strains was analyzed. in contrast to previously studied enteroviruses (enterovirus 71 and poliovirus), ev-d68 and human host have a high discr ...201627364082
a clinically authentic mouse model of enterovirus 71 (ev-a71)-induced neurogenic pulmonary oedema.enterovirus 71 (ev-a71) is a neurotropic virus that sporadically causes fatal neurologic illness among infected children. animal models of ev-a71 infection exist, but they do not recapitulate in animals the spectrum of disease and pathology observed in fatal human cases. specifically, neurogenic pulmonary oedema (npe)-the main cause of ev-a71 infection-related mortality-is not observed in any of these models. this limits their utility in understanding viral pathogenesis of neurologic infections. ...201627357918
pathologic studies of fatal encephalomyelitis in children caused by enterovirus 71.enterovirus 71 (ev71) is the major pathogen of hand, foot, and mouth disease and can cause death; however, its pathogenesis remains elusive.201627357294
in vitro assessment of combinations of enterovirus inhibitors against enterovirus 71.enterovirus 71 (ev-a71) is a major causative pathogen of hand, foot, and mouth disease (hfmd) epidemics. no antiviral therapies are currently available for treating ev-a71 infections. here, we selected five reported enterovirus inhibitors (suramin, itraconazole [itz], gw5074, rupintrivir, and favipiravir) with different mechanisms of action to test their abilities to inhibit ev-a71 replication alone and in combination. all selected compounds have anti-ev-a71 activities in cell culture. the combi ...201627353263
using a negative binomial regression model for early warning at the start of a hand foot mouth disease epidemic in dalian, liaoning province, china.the hand foot and mouth disease (hfmd) is a human syndrome caused by intestinal viruses like that coxsackie a virus 16, enterovirus 71 and easily developed into outbreak in kindergarten and school. scientifically and accurately early detection of the start time of hfmd epidemic is a key principle in planning of control measures and minimizing the impact of hfmd. the objective of this study was to establish a reliable early detection model for start timing of hand foot mouth disease epidemic in d ...201627348747
a monoclonal antibody to ameliorate central nervous system infection and improve survival in a murine model of human enterovirus-a71 encephalomyelitis.enterovirus a71 (ev-a71) encephalomyelitis is an often fatal disease for which there is no specific treatment available. passive immunization with a specific monoclonal antibody to ev-a71 was used on a murine model of ev-a71 encephalomyelitis to evaluate its therapeutic effectiveness before and after established central nervous system (cns) infection.201627340013
structural basis of viral rna-dependent rna polymerase catalysis and translocation.viral rna-dependent rna polymerases (rdrps) play essential roles in viral genome replication and transcription. we previously reported several structural states of the poliovirus rdrp nucleotide addition cycle (nac) that revealed a unique palm domain-based active site closure mechanism and proposed a six-state nac model including a hypothetical state representing translocation intermediates. using the rdrp from another human enterovirus, enterovirus 71, here we report seven rdrp elongation compl ...201627339134
clinical and associated immunological manifestations of hfmd caused by different viral infections in children.hand, foot, and mouth disease (hfmd), with vesiculae on the hands, feet and mouth, is an infectious disease caused by many viral pathogens. however, the differences of immune response induced by these pathogens are unclear. we compared the clinical manifestations and the levels of immunologic indicators from 60 hfmd patients caused by different viral pathogens to analyze the differences in the immune response. it was shown that th2 cytokines (il-4 and il-10) increased significantly in ev71-infec ...201627336013
cooperative effect of the vp1 amino acids 98e, 145a and 169f in the productive infection of mouse cell lines by enterovirus 71 (bs strain).enterovirus 71 (ev71) is a neurotrophic virus that causes hand, foot and mouth disease (hfmd) and occasional neurological infection among children. it infects primate cells but not rodent cells, primarily due to the incompatibility between the virus and the expressed form of its receptor, scavenger receptor class b member 2 (scarb2) protein, on rodent cells (mscarb2). we previously generated adapted strains (ev71:tllm and ev71:tllmv) that were shown to productively infect primate and rodent cell ...201627329847
gene expression and antiviral activity of interleukin-35 in response to influenza a virus infection.interleukin-35 (il-35) is a newly described member of the il-12 family. it has been reported to inhibit inflammation and autoimmune inflammatory disease and can increase apoptotic sensitivity. little is known about the role of il-35 during viral infection. herein, high levels of il-35 were found in peripheral blood mononuclear cells and throat swabs from patients with seasonal influenza a virus (iav) relative to healthy individuals. iav infection of human lung epithelial and primary cells increa ...201627307042
antiviral activity of micafungin against enterovirus 71.enterovirus 71 (ev71) is a major causative agent of hand-foot-mouth disease (hfmd) and also causes severe neurological complications, leading to fatality in young children. however, no effective therapy is currently available for the treatment of this infection.201627296985
interactome analysis of the ev71 5' untranslated region in differentiated neuronal cells sh-sy5y and regulatory role of fbp3 in viral replication.enterovirus 71 (ev71), a single-stranded rna virus, is one of the most serious neurotropic pathogens in the asia-pacific region. through interactions with host proteins, the 5' untranslated region (5'utr) of ev71 is important for viral replication. to gain a protein profile that interact with the ev71 5'utr in neuronal cells, we performed a biotinylated rna-protein pull-down assay in conjunction with lc-ms/ms analysis. a total of 109 proteins were detected and subjected to database for annotatio ...201627291656
discovery of 3-benzyl-1,3-benzoxazine-2,4-dione analogues as allosteric mitogen-activated kinase kinase (mek) inhibitors and anti-enterovirus 71 (ev71) agents.enterovirus 71 (ev71) is a kind of rna virus and one of the two causes of hand, foot and mouth disease (hfmd). inhibitors that target key components of ras/raf/mek/erk pathway in host cells could impair replication of ev71. a series of 3-benzyl-1,3-benzoxazine-2,4-diones were designed from a specific mek inhibitor g8935, by replacing the double bond between c3 and c4 within the coumarin scaffold with amide bond. one compound (9f) showed submicromolar inhibitory activity among the 12 derivatives. ...201627288186
human enterovirus 71 protein displayed on the surface of saccharomyces cerevisiae as an oral vaccine.human enterovirus 71 (ev-a71), a major agent of hand, foot, and mouth disease, has become an important public health issue in recent years. no effective antiviral or vaccines against ev-a71 infection are currently available. ev-a71 infection intrudes bodies through the gastric mucosal surface and it is necessary to enhance mucosal immune response to protect children from these pathogens. recently, the majority of ev-a71 vaccine candidates have been developed for parenteral immunization. however, ...201627259043
inhibitory effects of norwogonin, oroxylin a, and mosloflavone on enterovirus 71.severe complications associated with ev71 infections are a common cause of neonatal death. lack of effective therapeutic agents for these infections underlines the importance of research for the development of new antiviral compounds. in the present study, the anti-ev71 activity of norwogonin, oroxylin a, and mosloflavone from scutellaria baicalensis georgi was evaluated using a cytopathic effect (cpe) reduction method, which demonstrated that all three compounds possessed strong anti-ev71 activ ...201627257010
optimization of a class of tryptophan dendrimers that inhibit hiv replication leads to a selective, specific, and low-nanomolar inhibitor of clinical isolates of enterovirus a71.tryptophan dendrimers that inhibit hiv replication by binding to the hiv envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus a71. dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the brcr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low- ...201627246775
atp1b3: a virus-induced host factor against ev71 replication by up-regulating the production of type-i interferons.enterovirus 71 (ev71) infection can cause severe diseases, and is becoming increasingly common in children. in the current study, we carried out yeast two-hybrid assays to screen human proteins that could interact with 3a protein of ev71. human β3 subunit of na(+)/k(+)-atpase (atp1b3) protein was demonstrated to interact with the 3a protein of ev71. although 3a protein had no effect on the expression of atp1b3, ev71 infection resulted in elevated expression of atp1b3 in rd cell line, both on mes ...201627240146
design, synthesis, and biological evaluation of anti-ev71 agents.enterovirus 71 (ev71) is a major causative agent of hand, foot and mouth disease (hfmd), which can spread its infections to the central nervous and other systems with severe consequences. in this article, design, chemical synthesis, and biological evaluation of various anti-ev71 agents which incorporate michael acceptors are described. further sar study demonstrated that lactone type of michael acceptor provided a new lead of anti-ev71 drug candidates with high anti-ev71 activity in cell-based a ...201627234148
enterovirus 71 induces anti-viral stress granule-like structures in rd cells.stress granules (sgs) are dynamic cytoplasmic granules formed in response to a variety of stresses, including viral infection. several viruses can modulate the formation of sg with different effects, but the relationship between sg formation and ev71 infection is poorly understood. in this study, we report that ev71 inhibits canonical sgs formation in infected cells and induces the formation of novel rna granules that were distinguished from canonical sgs in composition and morphology, which we ...201627216457
cyclopiazonic acid, an inhibitor of calcium-dependent atpases with antiviral activity against human respiratory syncytial virus.human respiratory syncytial virus (rsv) is a common cause of lower respiratory tract infections in infants and young children worldwide, yet no vaccine or effective antiviral treatment is available. to search for new anti-rsv agents, we developed a cell-based assay that measures inhibition of rsv-induced cytopathic effect (cpe) and identified cyclopiazonic acid (cpa), an intracellular calcium atpase inhibitor as a rsv inhibitor (ec50 values 4.13 μm) by screening of natural product library. cpa i ...201627210812
enterovirus 71: a whole virion inactivated enterovirus 71 vaccine.enterovirus a71 (ev71) is the predominant causative agent of hand, foot, and mouth disease (hfmd), which is often associated with severe cases and even deaths. ev71-associated epidemics have emerged as a serious threat to public health, particularly in the asia-pacific region.201627206811
enhancing immune responses of ev71 vp1 dna vaccine by co-inoculating plasmid il-12 or gm-csf expressing vector in mice.enterovirus 71 (ev71) is a major causative viral agent for large outbreaks of hand, foot, and mouth disease in children and infants, yet there is no vaccine or effective antiviral treatment for severe ev71 infection. the immunogenicity of ev71 vp1 dna vaccine and the immunoregulatory activity of interleukin-12 (il-12) or granulocyte-monocyte colony stimulating factor (gm-csf) were investigated. dna vaccine plasmids, pcdna-vp1, pcdna-il-12 and pcdna-gm-csf were constructed and inoculated into bal ...201627188732
optimize the interactions at s4 with efficient inhibitors targeting 3c proteinase from enterovirus 71.enterovirus 71 (ev71) is the causative agent of hand, foot and mouth disease and can spread its infections to the central nervous and other systems with severe consequences. the replication of ev71 depends on its 3c proteinase (3c(pro) ), a significant drug target. by x-ray crystallography and functional assays, the interactions between inhibitors and ev71 3c(pro) were evaluated. it was shown that improved interactions at s4 for the substrate binding could significantly enhance the potency. a ne ...201627185390
a modular vaccine development platform based on sortase-mediated site-specific tagging of antigens onto virus-like particles.virus-like particles (vlps) can be used as powerful nanoscale weapons to fight against virus infection. in addition to direct use as vaccines, vlps have been extensively exploited as platforms on which to display foreign antigens for prophylactic vaccination and immunotherapeutic treatment. unfortunately, fabrication of new chimeric vlp vaccines in a versatile, site-specific and highly efficient manner is beyond the capability of traditional vlp vaccine design approaches, genetic insertion and c ...201627170066
genetic characterization of enterovirus 71 strains circulating in vietnam in 2012.enterovirus 71 subgenogroup c4 caused the largest outbreak of hand, foot and mouth disease (hfmd) in vietnam during 2011-2012, resulting in over 200,000 hospitalisations and 207 fatalities.201627148893
full-genome sequences of seven fatal enterovirus 71 strains isolated in shenzhen, china, in 2014.the whole-genome sequences of seven fatal enterovirus 71 (ev71) strains, isolated in southern china, in 2014, were determined. the complete genome sequences of these strains displayed close relationships to native ev71 strains and showed 94.2% to 99.8% identity to each other. all of these strains were assigned to subgenotype c4a based on phylogenetic analysis of the vp1 gene.201627125487
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