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susceptibility of human tonsillar epithelial cells to enterovirus 71 with normal cytokine response.a recent histopathologic study implicated human tonsillar crypt epithelium as an important site for ev71 replication in ev71-caused fatal cases. this study aimed to confirm the susceptibility of human tonsillar epithelium to ev71. two human tonsillar epithelial cell lines (ut-scc-60a and ut-scc-60b) were susceptive to ev71, and pi3k/akt, p38, erk1/2, and jnk1/2 signal pathways were activated. interferon-α, il-8, il-1β, il-6 and il-12p40 were induced and regulated by pi3k/akt, p38, erk1/2, and jn ...201627107253
a safe and sensitive enterovirus a71 infection model based on human scarb2 knock-in mice.enterovirus a71 infection has become a severe threat for global public health. vaccines for controlling and preventing enterovirus a71 epidemics are highly demanded, however, vaccine evaluation has been hindered by the lack of suitable enterovirus a71 infection animal models. here we established an hscarb2 knockin mouse model for real-time monitoring of enterovirus a71 infection in vivo. this model was sensitive to the infection of both replication-competent virus rev71(fy)-egfp and single round ...201627102822
alumina-encapsulated vaccine formulation with improved thermostability and immunogenicity.developing vaccine formulations with excellent thermostability and immunogenicity remains a great challenge. by in situ encapsulating a live-attenuated strain of human enterovirus 71 (ev71) in alumina, we obtained a robust vaccine formulation named ev71@nanoalum, which features significantly enhanced thermostability and immunogenicity. this attempt follows a material-based tactic for vaccine improvement.201627098047
in vitro and in vivo studies of a potent capsid-binding inhibitor of enterovirus 71.enterovirus 71 (ev-a71) is an important pathogen that can cause severe neurological symptoms and even death. our aim was to identify potent anti-ev-a71 compounds and study their underlying mechanisms and in vivo activity.201627098012
[etiology study on severe cases caused by hand-foot-mouth disease in children from henan province, 2014].to investigate the etiology of severe hand-foot-mouth disease (hfmd) in children in henan province.201627087228
structural characterization and antiviral activity of a novel heteropolysaccharide isolated from grifola frondosa against enterovirus 71.a novel heteropolysaccharide from grifola frondosa mycelia was extracted and purified using deae sephadex a-50 and sephadex g-200 chromatography. fourier transform infrared (ft-ir) spectroscopy and nuclear magnetic resonance ((1)h nmr and (13)c nmr) spectroscopy were used to decipher the structure of the purified g. frondosa polysaccharide (gfp1). chemical and spectral analysis revealed that gfp1, with an average molecular weight of 40.5kda, possessed a 1,6-β-d-glucan backbone with a single 1,3- ...201627083830
establishment of an animal challenge model as a potency assay for an inactivated enterovirus type 71 vaccine.enterovirus 71 (ev71) belongs to the enterovirus genus of the picornaviridae family, and its occurrence in asia is associated with hand-foot-and-mouth disease (hfmd), leading to death in some cases, in young children. an effective ev71 vaccine is therefore urgently needed. in this study, we established a two-step ev71 vaccine potency model. intraperitoneal injections in 2-day-old suckling mice were used to establish the ld50 of ev71 b4, b5, c2, c4, and c5 subgenotypes. only c4 caused hind limb p ...201627068365
milrinone in enterovirus 71 brain stem encephalitis.enterovirus 71 (ev71) was implicated in a widespread outbreak of hand-foot-and-mouth disease (hfmd) across the asia pacific area since 1997 and has also been reported sporadically in patients with brain stem encephalitis. neurogenic shock with pulmonary edema (pe) is a fatal complication of ev71 infection. among inotropic agents, milrinone is selected as a therapeutic agent for ev71- induced pe due to its immunopathogenesis. milrinone is a type iii phosphodiesterase inhibitor that has both inotr ...201627065870
susceptibilities of enterovirus d68, enterovirus 71, and rhinovirus 87 strains to various antiviral compounds.compounds were evaluated for antiviral activity in rhabdomyosarcoma (rd) cells against a recent 2014 clinical isolate of enterovirus d68 (ev-d68), a 1962 strain of ev-68d, rhinovirus 87 (rv-87, serologically the same as ev-d68), and enterovirus 71 (ev-71). test substances included known-active antipicornavirus agents (enviroxime, guanidine hcl, pirodavir, pleconaril, and rupintrivir), nucleobase/nucleoside analogs (3-deazaguanine and ribavirin), and three novel epidithiodiketopiperazines (kcn-2, ...201627063860
the nuclear protein sam68 is recruited to the cytoplasmic stress granules during enterovirus 71 infection.our previous study found that the nuclear protein, 68-kda src-associated in mitosis protein (sam68), is translocated to the cytoplasm and forms punctate pattern during enterovirus 71 (ev71) infection [virus research, 180 (2014), 1-11]. however, the exact function of this punctate pattern in cytoplasm during ev71 infection remains unknown. in this study, we firstly have examined this punctate pattern of sam68 re-localization in the cytoplasm, and observed the obvious recruitments of sam68 to the ...201627057671
elevated expression of circulating mir876-5p is a specific response to severe ev71 infections.human enterovirus 71 (ev71) is a major causative agent of hand, foot, and, mouth disease, accounting for more than 65% of recent outbreaks. following enteroviral infection, the host responses are crucial indicators for the development of a diagnosis regarding the clinical severity of ev71 infections. in this study, we implemented nanostring ncounter technology to characterize the responses of serum microrna (mirna) profiles to various ev71 infection diseases. upon ev71 infection, 44 mirnas were ...201627052555
correction: routine pediatric enterovirus 71 vaccination in china: a cost-effectiveness analysis.[this corrects the article doi: 10.1371/journal.pmed.1001975.].201627050103
genetic evolution of human enterovirus a71 subgenotype c4 in shenzhen, china, 1998-2013.human enterovirus a71 (ev-a71) is one of the severest enteroviruses that causes hand, foot, and mouth disease (hfmd) among children. this study identified the mutations of ev-a71 vp1 amino acid residues over a number of years and explored the possible association of identified mutations and hfmd epidemic outbreaks in shenzhen, china.201627038503
genomic and immunologic factors associated with viral pathogenesis in a lethal ev71 infected neonatal mouse model.hand, foot and mouth disease (hfmd) caused by enterovirus 71 (ev71) has emerged as a major health problem in china and worldwide. the present study aimed to understand the virological features of ev71 and host responses resulting from ev71 infection. six different ev71 strains were isolated from hfmd patients with severe or mild clinical symptoms, and were analyzed for pathogenicity in vitro and in vivo. the results demonstrated that the six virus strains exhibited similar cytopathogenic effects ...201627035332
pulmonary and central nervous system pathology in fatal cases of hand foot and mouth disease caused by enterovirus a71 infection.in the past 17 years, neurological disease associated with enterovirus a71 (ev-a71) has increased dramatically in the asia-pacific region with a high fatality rate in young infants, often due to pulmonary oedema, however the mechanism of this oedema remains obscure. we analysed the brainstem, heart and lungs of 15 fatal cases of confirmed ev-a71 infection in order to understand the pathophysiological mechanism of death and pulmonary oedema. in keeping with other case studies, the main cause of d ...201627020504
cyclical patterns of hand, foot and mouth disease caused by enterovirus a71 in malaysia.enterovirus a71 (ev-a71) is an important emerging pathogen causing large epidemics of hand, foot and mouth disease (hfmd) in children. in malaysia, since the first ev-a71 epidemic in 1997, recurrent cyclical epidemics have occurred every 2-3 years for reasons that remain unclear. we hypothesize that this cyclical pattern is due to changes in population immunity in children (measured as seroprevalence). neutralizing antibody titers against ev-a71 were measured in 2,141 residual serum samples coll ...201627010319
differential regulation of tlr signaling on the induction of antiviral interferons in human intestinal epithelial cells infected with enterovirus 71.enterovirus 71 (ev71) causes hand-foot-and-mouth disease, which can lead to fatal neurological complications in young children and infants. few gastrointestinal symptoms are observed clinically, suggesting the presence of a unique immunity to ev71 in the gut. we reported a robust induction of interferons (ifns) in human intestinal epithelial cells (ht-29), which was suppressed in other types such as rd and hela cells. the underlying mechanism for the apparent difference remains obscure. in this ...201627007979
gan-lu-siao-du-yin, a prescription of traditional chinese medicine, inhibited enterovirus 71 replication, translation, and virus-induced cell apoptosis.gan-lu-siao-du-yin (glsdy) is a prescription of traditional chinese medicine. glsdy contains 11 ingredients and is commonly used for endemic diseases. enterovirus 71 (ev71) is an endemic disease that can cause meningoencephalitis with mortality and neurologic sequelae without any effective management. it is unknown whether glsdy is effective against ev71 infection.201626993050
fragment-wise design of inhibitors to 3c proteinase from enterovirus 71.enterovirus 71 (ev71) is a causative agent of hand, foot and mouth disease (hfmd), which can spread its infection to central nervous and other systems with severe consequence. a key factor in the replication of ev71 is its 3c proteinase (3c(pro)), a significant drug target. peptidomimetics were employed as inhibitors of this enzyme for developing antivirals. however, the peptide bonds in these peptidomimetics are a source of low bioavailability due to their susceptibility to protease digestion. ...201626987809
enterovirus a71 genogroups c and e in children with acute flaccid paralysis, west africa. 201626982072
routine pediatric enterovirus 71 vaccination in china: a cost-effectiveness analysis.china accounted for 87% (9.8 million/11.3 million) of all hand, foot, and mouth disease (hfmd) cases reported to who during 2010-2014. enterovirus 71 (ev71) is responsible for most of the severe hfmd cases. three ev71 vaccines recently demonstrated good efficacy in children aged 6-71 mo. here we assessed the cost-effectiveness of routine pediatric ev71 vaccination in china.201626978565
bpifb6 regulates secretory pathway trafficking and enterovirus replication.bactericidal/permeability-increasing protein (bpi) fold-containing family b, member 3 (bpifb3) is an endoplasmic reticulum (er)-localized host factor that negatively regulates coxsackievirus b (cvb) replication through its control of the autophagic pathway. here, we show that another member of the bpifb family, bpifb6, functions as a positive regulator of cvb, and other enterovirus, replication by controlling secretory pathway trafficking and golgi complex morphology. we show that similar to bpi ...201626962226
[role of toll-like receptor 7 in the production of inflammatory cytokines in ev-a71-infected human jurkat t cells].to investigate the expression of toll-like receptor (tlr) mrna in enterovirus 71(ev-a71) infected human jurkat t cells and clarify the role of tlrs in the pathogenesis of ev-a71 infection-induced inflammation.201626957247
structural basis for recognition of human enterovirus 71 by a bivalent broadly neutralizing monoclonal antibody.enterovirus 71 (ev71) is the main pathogen responsible for hand, foot and mouth disease with severe neurological complications and even death in young children. we have recently identified a highly potent anti-ev71 neutralizing monoclonal antibody, termed d5. here we investigated the structural basis for recognition of ev71 by the antibody d5. four three-dimensional structures of ev71 particles in complex with igg or fab of d5 were reconstructed by cryo-electron microscopy (cryo-em) single parti ...201626938634
mri signal intensity differentiation of brainstem encephalitis induced by enterovirus 71: a classification approach for acute and convalescence stages.the objective of this study is to assess standardized histograms of signal intensities of t1 signal and t2 signal on sagittal view without enhancement during (1) acute stage, and (2) convalescence stage of pediatric patients with enterovirus 71 related brainstem encephalitis (be), and with respect to (3) healthy normal.201626917424
pilot surveillance for childhood encephalitis in australia using the paediatric active enhanced disease surveillance (paeds) network.we aimed to assess the performance of active surveillance for hospitalized childhood encephalitis in new south wales (nsw) using the paediatric active enhanced disease surveillance (paeds) network to inform methodology for the nationwide australian childhood encephalitis (ace) study. we piloted active surveillance for suspected encephalitis from may to december 2013 at the children's hospital at westmead, sydney, nsw. cases were ascertained using four screening methods: weekday nurse screening o ...201626916674
synthesis and structure-activity relationship of α-keto amides as enterovirus 71 3c protease inhibitors.α-keto amide derivatives as enterovirus 71 (ev71) 3c protease (3c(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. structure-activity relationship (sar) study indicated that small moieties were primarily tolerated at p1' and the introduction of para-fluoro benzyl at p2 notably improved the potency of inhibitor. inhibitors 8v, 8w and 8x exhibited satisfactory activity (ic50=1.32±0.26μm, 1.88±0.35μm and 1.52±0.31μm, respectively) and favorable cc50 ...201626916437
pyruvate carboxylase activates the rig-i-like receptor-mediated antiviral immune response by targeting the mavs signalosome.when retinoic acid-inducible gene 1 protein (rig-i)-like receptors sense viral dsrna in the cytosol, rig-i and melanoma differentiation-associated gene 5 (mda5) are recruited to the mitochondria to interact with mitochondrial antiviral signaling protein (mavs) and initiate antiviral immune responses. in this study, we demonstrate that the biotin-containing enzyme pyruvate carboxylase (pc) plays an essential role in the virus-triggered activation of nuclear factor kappa b (nf-κb) signaling mediat ...201626906558
intravenous magnesium sulfate for the management of severe hand, foot, and mouth disease with autonomic nervous system dysregulation in vietnamese children: study protocol for a randomized controlled trial.over the last 15 years, hand, foot, and mouth disease (hfmd) has emerged as a major public health burden across the asia-pacific region. a small proportion of hfmd patients, typically those infected with enterovirus 71 (ev71), develop brainstem encephalitis with autonomic nervous system (ans) dysregulation and may progress rapidly to cardiopulmonary failure and death. although milrinone has been reported to control hypertension and support myocardial function in two small studies, in practice, a ...201626896318
[analysis of seroepidemiology of enterovirus 71 diseases in children in jiangsu province].to analyze the dynamic pattern and the distributive characteristics of neutralizing antibody against enterovirus 71 (ev-a71 ) in children aged 6-35 months in jiangsu province from 2012 to 2014.201526887297
sirna targeting the 2apro genomic region prevents enterovirus 71 replication in vitro.enterovirus 71 (ev71) is the most important etiological agent of hand, foot, and mouth disease (hfmd) in young children, which is associated with severe neurological complications and has caused significant mortalities in recent hfmd outbreaks in asia. however, there is no effective antiviral therapy against ev71. in this study, rna interference (rnai) was used as an antiviral strategy to inhibit ev71 replication. three small interfering rnas (sirnas) targeting the 2apro region of the ev71 genom ...201626886455
identification and structure-activity relationships of diarylhydrazides as novel potent and selective human enterovirus inhibitors.enterovirus 71 (ev71) plays an important role in hand-foot-and-mouth disease. in this study, a series of diarylhydrazide analogues was synthesized, and the systematic exploration of sar led to potent enterovirus inhibitors, of which compound 15 exhibits significant improvements in inhibition potency with an ec50 value of 0.02 μm against ev71. it is very interesting that this class of diarylhydrazides exhibits activities against a series of human enteroviruses at the picomolar level, including ev ...201626885567
analysis on the sequence of the whole genome of an isolated enterovirus 71 strain.an enterovirus 71 (ev71) strain query was isolated from a patient specimen in 2015. in order to known about its genetic evolution, this study amplified gene fragment of the isolated stain by rt-pct and carried out sequencing of the total genome. the homology and genetic evolution of the gene sequence of the virus strain in the study were analyzed. the results showed that the isolated ev71 strain in this study had higher homology of nucleotide sequence and amino acid sequence with other virus str ...201526884986
clinical efficacy of therapy with recombinant human interferon α1b in hand, foot, and mouth disease with enterovirus 71 infection.a rapid expansion of hfmd with enterovirus 71 infection outbreaks has occurred and caused deaths in recent years in china, but no vaccine or antiviral drug is currently available for ev71 infection. this study aims to provide treatment programs for hfmd patients. we conducted a randomized, double-blind, controlled trial and evaluated clinical efficacy of therapy with rhuifn-α1b in hfmd patients with ev71 infection. there were statistical differences in outcomes including the fever clearance time ...201626882102
idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site.enterovirus 71 (ev71) causes life-threatening diseases with neurological manifestations in young children. however, the treatment of ev71 infections remains an unmet medical need. idarubicin (idr) is an anthracycline compound that is used therapeutically for certain types of tumour. in this study, we identified idr as an ev71 inhibitor, which displayed antiviral potency in the submicromolar range and substantially protected cells from the cytopathic effects and cell death caused by ev71 infectio ...201626879094
pancreatitis in hand-foot-and-mouth disease caused by enterovirus 71.some viruses, including certain members of the enterovirus genus, have been reported to cause pancreatitis, especially coxsackie virus. however, no case of human enterovirus 71 (ev71) associated with pancreatitis has been reported so far. we here report a case of ev71-induced hand-foot-and-mouth disease (hfmd) presenting with pancreatitis in a 2-year-old girl. this is the first report of a patient with acute pancreatitis in hfmd caused by ev71. we treated the patient conservatively with nasogast ...201626877620
carnitine palmitoyl transferase 2 polymorphism may be associated with enterovirus 71 severe infection in a chinese population.genetic polymorphism in the carnitine palmitoyl transferase 2 (cpt2) gene has been reported to be a susceptibility factor in a number of syndromes of acute encephalopathy with various infectious diseases, but evidence of its effect on enterovirus 71 (ev71) infection is lacking. the goal of this study was to examine the relationship between genetic polymorphism of cpt2 and severity of ev71 infection in a chinese population. pcr of five exons of the cpt2 gene was carried out to identify single-nuc ...201626874509
luteoloside acts as 3c protease inhibitor of enterovirus 71 in vitro.luteoloside is a member of the flavonoids family that exhibits several bioactivities including anti-microbial and anti-cancer activities. however, the antiviral activity of luteoloside against enterovirus 71 (ev71) and the potential mechanism(s) responsible for this effect remain unknown. in this study, the antiviral potency of luteoloside against ev71 and its inhibitory effects on 3c protease activity were evaluated. first, we investigated the cytotoxicity of luteoloside against rhabdomyosarcom ...201626870944
risk factors for enterovirus a71 seropositivity in rural indigenous populations in west malaysia.enterovirus a71 (ev-a71), which is transmitted by the fecal-oral route, causes hand, foot and mouth disease and, rarely, severe neurological complications. in malaysia, the indigenous rural community (orang asli) has a high prevalence of parasitic diseases due to poor sanitation, water supply and hygiene practices. this cross-sectional study compared the seroepidemiology of ev-a71 among rural orang asli and urban kuala lumpur populations in west malaysia, and determined the risk factors associat ...201626866912
impact of human enterovirus 71 genotypes in meningoencephalitis in iran.since the importance of poliovirus has diminished, as a result of its elimination in the majority of countries, non-polioviruses are emerging as causative agents of severe central nervous system (cns) involvement. outbreaks of enterovirus 71 (ev71)-associated cns infections have recently been reported in asia, australia, and europe.201526865943
modification of the length and structure of the linker of n(6)-benzyladenosine modulates its selective antiviral activity against enterovirus 71.very recently, we demonstrated that n(6)-isopentenyladenosine, a cytokinin nucleoside, exerts a potent and selective antiviral effect on the replication of human enterovirus 71. the present study is devoted to the structure optimization of another natural compound: n(6)-benzyladenosine. we mainly focused on the exploration of the size and nature of the linker between the adenine and the phenyl ring, as well as on the necessity of the d-ribose residue. more than 30 analogues of n(6)-benzyladenosi ...201626854380
oblongifolin m, an active compound isolated from a chinese medical herb garcinia oblongifolia, potently inhibits enterovirus 71 reproduction through downregulation of erp57.there is no effective drug to treat ev71 infection yet. traditional chinese herbs are great resources for novel antiviral compounds. here we showed that oblongifolin m (om), an active compound isolated from garcinia oblongifolia, potently inhibited ev71 infection in a dose dependent manner. to identify its potential effectors in the host cells, we successfully identified 18 proteins from 52 differentially expressed spots by comparative proteomics studies. further studies showed that knockdown of ...201626848777
high-throughput characterization of virus-like particles by interlaced size-exclusion chromatography.the development and manufacturing of safe and effective vaccines relies essentially on the availability of robust and precise analytical techniques. virus-like particles (vlps) have emerged as an important and valuable class of vaccines for the containment of infectious diseases. vlps are produced by recombinant protein expression followed by purification procedures to minimize the levels of process- and product-related impurities. the control of these impurities is necessary during process deve ...201626845741
enterovirus 71 transmission by exosomes establishes a productive infection in human neuroblastoma cells.exosomes are small secreted cellular vesicles for intercellular communications which contain proteins, mrnas, and micrornas (mirnas). recent studies have shown that exosomes play an important role in the transmission of infectious agents including hepatitis c virus, human immunodeficiency virus, and so on. however, the role of exosomes in the transfer of enterovirus 71 (ev71) between host cells remains unknown. in this study, we show that the exosomes derived from ev71-infected rhabdomyosarcoma ...201626837894
comprehensive safety assessment of a human inactivated diploid enterovirus 71 vaccine based on a phase iii clinical trial.human enterovirus 71 (ev71) is a causative agent of hand, foot, and mouth disease (hfmd). in a previous phase iii trial in children, a human diploid cell-based inactivated ev71 vaccine elicited ev71 specific immune responses and protection against ev71 associated hfmd. this study aimed to assess the factors influencing the severity of adverse events observed in this previous trial. this was a randomized, double-blinded, placebo-controlled, phase iii clinical trial of a human diploid vaccine carr ...201626837471
chinese herbal medicines as a source of molecules with anti-enterovirus 71 activity.enterovirus 71 (ev71) is one of the causative agents of hand, foot, and mouth disease (hfmd), which sometimes leads to severe neurological disease and death in the asia-pacific region. in chinese medicine, hfmd is caused mainly by an accumulation of damp-heat and toxicity in the body. no effective drugs are currently available for the treatment and prevention of ev71 infection. this review summarizes the potential chinese herbal extracts and isolated compounds with antiviral activity against ev7 ...201626834824
the autophagic machinery in enterovirus infection.the enterovirus genus of the picornaviridae family comprises many important human pathogens, including polioviruses, rhinovirus, enterovirus a71, and enterovirus d68. they cause a wide variety of diseases, ranging from mild to severe life-threatening diseases. currently, no effective vaccine is available against enteroviruses except for poliovirus. enteroviruses subvert the autophagic machinery to benefit their assembly, maturation, and exit from host. some enteroviruses spread between cells via ...201626828514
a consistent orally-infected hamster model for enterovirus a71 encephalomyelitis demonstrates squamous lesions in the paws, skin and oral cavity reminiscent of hand-foot-and-mouth disease.enterovirus a71 (ev-a71) causes self-limiting, hand-foot-and-mouth disease (hfmd) that may rarely be complicated by encephalomyelitis. person-to-person transmission is usually by fecal-oral or oral-oral routes. to study viral replication sites in the oral cavity and other tissues, and to gain further insights into virus shedding and neuropathogenesis, we developed a consistent, orally-infected, 2-week-old hamster model of hfmd and ev-a71 encephalomyelitis. tissues from orally-infected, 2-week-ol ...201626815859
ev71 virus-like particles produced by co-expression of capsid proteins in yeast cells elicit humoral protective response against ev71 lethal challenge.enterovirus 71 (ev71) is the most common causative pathogens of hand, foot and mouth disease (hfmd) associated with severe neurological complications. there is a great need to develop prophylactic vaccine against ev71 infection.201626809443
clinical characteristics and functional motor outcomes of enterovirus 71 neurological disease in children.enterovirus 71 (ev71) causes a spectrum of neurological complications with significant morbidity and mortality. further understanding of the characteristics of ev71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines.201626785318
innate immunity evasion by enteroviruses: insights into virus-host interaction.enterovirus genus includes multiple important human pathogens, such as poliovirus, coxsackievirus, enterovirus (ev) a71, ev-d68 and rhinovirus. infection with evs can cause numerous clinical conditions including poliomyelitis, meningitis and encephalitis, hand-foot-and-mouth disease, acute flaccid paralysis, diarrhea, myocarditis and respiratory illness. evs, which are positive-sense single-stranded rna viruses, trigger activation of the host antiviral innate immune responses through pathogen re ...201626784219
genome analysis of enterovirus 71 strains differing in mouse pathogenicity.enterovirus 71 (ev71) is a major causative agent of hand, foot, and mouth disease (hfmd) and is occasionally associated with severe neurological diseases. the investigation of virulence determinants of ev71 is rudimentary. therefore, it is important to understand the relationship between ev71 virulence and genomic information. in this study, a series of analyses about full-length genomic sequence were performed on six ev71 strains isolated from hfmd patients with either severe or mild clinical s ...201626781949
validation and evaluation of serological correlates of protection for inactivated enterovirus 71 vaccine in children aged 6-35 months.a primary goal of this study was to establish the serological mechanistic correlate of protection (mcop) for an inactivated enterovirus 71 (ev71) vaccine.201626751765
pluripotent human embryonic stem cell derived neural lineages for in vitro modelling of enterovirus 71 infection and therapy.the incidence of neurological complications and fatalities associated with hand, foot & mouth disease has increased over recent years, due to emergence of newly-evolved strains of enterovirus 71 (ev71). in the search for new antiviral therapeutics against ev71, accurate and sensitive in vitro cellular models for preliminary studies of ev71 pathogenesis is an essential prerequisite, before progressing to expensive and time-consuming live animal studies and clinical trials.201626738773
[inactivation of ev71 by exposure to heat and ultraviolet light].enterovirus 71 (ev71) is a major agent of hand, foot and mouth disease that can cause a severe burden of disease to children. to identify an effective method for the control and prevention of ev71, we studied the effect of exposure to heat and ultraviolet (uv) light upon ev71 inactivation. we found that exposure to 50 degrees c could not inactivate the infectivity of ev71. however, exposure to 60 degrees c and 70 degrees c could inactivate ev71 effectively. ev71 could be inactivated after exposu ...201526738287
interferon-mediated antiviral activities of angelica tenuissima nakai and its active components.angelica tenuissima nakai is a widely used commodity in traditional medicine. nevertheless, no study has been conducted on the antiviral and immune-modulatory properties of an aqueous extract of angelica tenuissima nakai. in the present study, we evaluated the antiviral activities and the mechanism of action of an aqueous extract of angelica tenuissima nakai both in vitro and in vivo. in vitro, an effective dose of angelica tenuissima nakai markedly inhibited the replication of influenza a virus ...201626727903
antiviral effects of reduning injection against enterovirus 71 and possible mechanisms of action.the present study was designed to evaluate the protective effects of reduning injection against enterovirus 71 (ev71) in vero cells and in mice. the vero cells were infected with 100 and 50 tcid50 (50% tissue culture infective dose) of ev71, respectively. the inhibition of reduning injection on cytopathic effect (cpe) was detected. meanwhile, a mouse model produced by intraperitoneal ev71-infection (10(6) tcid50), was used to investigate the protective effects of reduning injection. the total su ...201526721706
glucose-6-phosphate dehydrogenase enhances antiviral response through downregulation of nadph sensor hscarg and upregulation of nf-κb signaling.glucose-6-phosphate dehydrogenase (g6pd)-deficient cells are highly susceptible to viral infection. this study examined the mechanism underlying this phenomenon by measuring the expression of antiviral genes-tumor necrosis factor alpha (tnf-α) and gtpase myxovirus resistance 1 (mx1)-in g6pd-knockdown cells upon human coronavirus 229e (hcov-229e) and enterovirus 71 (ev71) infection. molecular analysis revealed that the promoter activities of tnf-α and mx1 were downregulated in g6pd-knockdown cell ...201526694452
seroepidemiology of human enterovirus 71 infection among children, cambodia.enterovirus 71 is reported to have emerged in cambodia in 2012; at least 54 children with severe encephalitis died during that outbreak. we used serum samples collected during 2000-2011 to show that the virus had been widespread in the country for at least a decade before the 2012 outbreak.201626690000
a functional polymorphism in ifnar1 gene is associated with susceptibility and severity of hfmd with ev71 infection.enterovirus 71 (ev71), one of the major pathogens of hand, foot and mouth disease (hfmd), results in millions of infections and hundreds of deaths each year in southeast asia. biased infection and variable clinical manifestations of ev71 hfmd indicated that host genetic background played an important role in the occurrence and development of the disease. we identified the mrna profiles of ev71 hfmd patients, which type i interferon (ifn) pathway related genes were down-regulated. four single nuc ...201526679744
recent progress towards novel ev71 anti-therapeutics and vaccines.enterovirus 71 (ev71) is a group of viruses that belongs to the picornaviridae family, which also includes viruses such as polioviruses. ev71, together with coxsackieviruses, is widely known for its association with hand foot mouth disease (hfmd), which generally affects children age five and below. besides hfmd, ev71 can also trigger more severe and life-threatening neurological conditions such as encephalitis. considering the lack of a vaccine and antiviral drug against ev71, together with the ...201526670245
studies on inhibition of proliferation of enterovirus-71 by compound yz-ly-0.in recent years, hand-foot-and-mouth disease (hfmd), which is caused by enteroviruses, has emerged as a serious illness. it affects mainly children under the age of five and results in high fatality rates. enterovirus 71 (ev71) is the main causative agent of hfmd in china and currently there are no effective anti-viral drugs available to treat hfmd. in the present study, we screened compounds for inhibition of proliferation of ev71. compound yz-ly-0 stalled the life cycle of ev71. the inhibitor ...201526640412
relationship between serologic response and clinical symptoms in children with enterovirus 71-infected hand-foot-mouth disease.this study aimed to explore the correlation between clinical symptoms, including rash and fever, and serum antibody reaction to enterovirus 71 (ev71) infection in children hospitalized due to hand-foot-mouth disease (hfmd). from may 2014 to july 2014, a total of 547 children hospitalized due to hfmd in children's hospital of fudan university were enrolled retrospectively. rna levels of ev71 and ca16 in fecal, serum, and cerebrospinal fluid specimens were measured using quantitative real-time rt- ...201526617898
[inosine pranobex - cytotoxic activities and effect of on replication of human parainfluenza viruses (hpiv-2, hpiv-4), entroviruses (ca16, ev71) and adenoviruses (hadv-2, hadv-5) in vitro].there are no specific antivirals designed for many viral infections. inosine pranobex (pi) is a purine nucleoside that is involved in a wide variety of intracellular biochemical processes. the mechanism of action in human body is still unclear but numerous studies have demonstrated that this drug inhibits viral replication and exhibit pleiotropic effect. we evaluated in vitro effect of inosine pranobex (pi) on replication of human viruses: parainfluenza viruses (hpiv-2, hpiv-4), entroviruses a ( ...201526591662
association between angiopoietin-2 and enterovirus 71 induced pulmonary edema.to characterize pulmonary edema (pe) fluid induced by enterovirus 71 (ev71) infection, elucidate the relationship between angiopoietin-2 (ang-2) and pe, and explore the pathogenesis of pe.201626590154
engineering enhanced vaccine cell lines to eradicate vaccine-preventable diseases: the polio end game.vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. to enhance vaccine production at reduced costs, a genome-wide rna interference (rnai) screen was performed to identify gene knockdown events that enhanced poliovirus replication. primary screen hits were validated in a vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. multiple single and dual gene silencing events i ...201526581994
host microrna mir-197 plays a negative regulatory role in the enterovirus 71 infectious cycle by targeting the ran protein.enterovirus 71 (ev71), a member of picornaviridae, is associated with severe central nervous system complications. in this study, we identified a cellular microrna (mirna), mir-197, whose expression was downregulated by viral infection in a time-dependent manner. in mir-197 mimic-transfected cells, ev71 replication was inhibited, whereas the internal ribosome entry site (ires) activity was decreased in ev71 strains with or without predicted mir-197 target sites, indicating that mir-197 targets h ...201526581983
cyanohydrin as an anchoring group for potent and selective inhibitors of enterovirus 71 3c protease.cyanohydrin derivatives as enterovirus 71 (ev71) 3c protease (3c(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. compared with the reported inhibitors, cyanohydrins (1s,2s,2's,5s)-16 and (1r,2s,2's,5s)-16 exhibited significantly improved activity and attractive selectivity profiles against other proteases, which were a result of the specific interactions between the cyanohydrin moiety and the catalytic site of 3c(pro). cyanohydrin as an anchorin ...201526571192
a dynamic model for the outbreaks of hand, foot, and mouth disease in taiwan.the first large outbreak of hand, foot, and mouth disease (hfmd) with severe complications primarily caused by enterovirus 71 was reported in taiwan in 1998. surveillance of hfmd to evaluate the spread of hfmd with and without infection control policy is needed. we developed a new dynamic epidemic susceptible-infected-recovered (sir) model to fit the surveillance data on containing valuable information on the severity of hfmd in order to accurately estimate the basic reproductive number (r 0) of ...201626567705
identification, synthesis and pharmacological evaluation of novel anti-ev71 agents via cyclophilin a inhibition.in this work, the relationship between cyclophilin a (cypa) and ev71 prompted us to screen a series of small molecular cypa inhibitors which were previously reported by our group. among them, compounds 1 and 2 were discovered as non-immunosuppressive anti-ev71 agents with an ec50 values of 1.07±0.17μm and 3.36±0.45μm in virus assay, respectively, which were desirably for the further study. the subsequent chemical modifications derived a novel class of molecules, among which compound 11 demonstra ...201526564266
antiviral activities of several oral traditional chinese medicines against influenza viruses.influenza is still a serious threat to human health with significant morbidity and mortality. the emergence of drug-resistant influenza viruses poses a great challenge to existing antiviral drugs. traditional chinese medicines (tcms) may be an alternative to overcome the challenge. here, 10 oral proprietary chinese medicines were selected to evaluate their anti-influenza activities. these drugs exhibit potent inhibitory effects against influenza a h1n1, influenza a h3n2, and influenza b virus. i ...201526557857
biological characteristics of different epidemic enterovirus 71 strains and their pathogeneses in neonatal mice and rhesus monkeys.hand, foot and mouth disease (hfmd) has been prevalent in china since 2008. enterovirus 71 (ev71) is a common causative agent of hfmd, and various strains of ev71 are prevalent worldwide. the ev71c4 subgenotype is the most endemic strain in china. however, few studies investigating the biological characteristics and pathogeneses of different c4 strains have been reported. therefore, the current study investigated 19 clinical ev71 strains in neonatal icr mice and neonatal rhesus monkeys by compar ...201626555165
transmission patterns of human enterovirus 71 to, from and among european countries, 2003 to 2013.enterovirus 71 (ev-71) is involved in epidemics of hand, foot, and mouth disease (hfmd) and has been reported to occur with severe neurological complications in eastern and south-east asia. in other geographical areas, the transmission of this virus is poorly understood. we used large sequence datasets (of the gene encoding the viral protein 1, vp1) and a bayesian phylogenetic approach to compare the molecular epidemiology and geographical spread patterns of ev-71 subgenogroups b4, b5, c1, c2, a ...201526530407
pros and cons of vp1-specific maternal igg for the protection of enterovirus 71 infection.enterovirus 71 (ev71) causes hand, foot, and mouth diseases and can result in severe neurological disorders when it infects the central nervous system. thus, there is a need for the development of effective vaccines against ev71 infection. here we report that viral capsid protein 1 (vp1), one of the main capsid proteins of ev71, efficiently elicited vp1-specific immunoglobulin g (igg) in the serum of mice immunized with recombinant vp1. the vp1-specific igg produced in female mice was efficientl ...201526529069
[progress in research on structure, function and antiviral of enterovirus a71 3c protein].enterovirus a71 (ev-a71) causes hand, foot, and mouth disease (hfmd) and various neurological complications, including aseptic meningitis and neurogenic pulmonary edema in young children. hfmd caused by ev-a71 have broken out several times in the asia-pacific region since 2007. and it has been a serious threat to public health. there is no effective vaccine or antiviral drug. the pathogenesis of ev-a71 infection is unknown, and ev-a71 3c protein plays an irreplaceable role in replication and ant ...201526524922
risk factors for severe hand foot mouth disease in singapore: a case control study.hand foot mouth disease (hfmd) is a common childhood infection that can potentially lead to serious complications. the aim of this study is to identify risk factors of acquiring severe hfmd in our population.201526520791
enterovirus 71 induces autophagy by regulating has-mir-30a expression to promote viral replication.enterovirus 71 (ev71), the etiological agent of hand-foot-and-mouth disease, has increasingly become a public health challenge around the world. previous studies reported that ev71 infection can induce autophagic machinery to enhance viral replication in vitro and in vivo, but did not address the underlying mechanisms. increasing evidence suggests that autophagy, in a virus-specific manner, may function to degrade viruses or facilitate viral replication. in this study, we reported that ev71 infe ...201526515789
identification of positively charged residues in enterovirus 71 capsid protein vp1 essential for production of infectious particles.enterovirus 71 (ev71), a positive-stranded rna virus, is the major cause of hand, foot, and mouth disease (hfmd) in children, which can cause severe central nervous system disease and death. the capsids of ev71 consist of 60 copies of each of four viral structural proteins (vp1 to vp4), with vp1, vp2, and vp3 exposed on the surface and vp4 arranged internally. vp1 plays a central role in particle assembly and cell entry. to gain insight into the role of positively charged residues in vp1 functio ...201526512078
impact of il-8-251a/t gene polymorphism on severity of disease caused by enterovirus 71 infection.the study was performed in ev71-infected patients, with 97 mild cases and 80 severe cases. il-8251a/t genotypes were determined by the polymerase chain reaction restriction fragment length polymorphism technique. severe cases had a significantly higher frequency of the il8-251 at and tt genotypes than mild cases (52.5 % vs. 49.5 % and 42.5 % vs. 30.9 %, respectively; p = 0.024). the frequency of il-8-251t alleles among the severe cases was also significantly higher than that of mild cases (68.7  ...201626497182
[expression and significance of toll-like receptors 7 and 8 in brain and lung tissues of death cases caused by ev71 infection].to study the significance of toll-like receptors (tlr) -7 and -8 in the pathogenesis of infection caused by enterovirus type 71 (ev71) through measuring the expression of tlr7 and tlr8 in brain and lung tissues from the death cases caused by ev71 infection.201526483222
comparing the primary and recall immune response induced by a new ev71 vaccine using systems biology approaches.three inactivated ev71 whole-virus vaccines have completed phase iii clinical trials in mainland china, with high efficacy, satisfactory safety, and sustained immunogenicity. however, the molecular mechanisms how this new vaccine elicit potent immune response remain poorly understood. to characterize the primary and recall responses to ev71 vaccines, pbmc from 19 recipients before and after vaccination with ev71 vaccine are collected and their gene expression signatures after stimulation with ev ...201526465882
two-year efficacy and immunogenicity of sinovac enterovirus 71 vaccine against hand, foot and mouth disease in children.to evaluate the efficacy and immunogenicity of the sinovac enterovirus 71 (ev71) vaccine for up to two years.201626460695
intestinal detoxification time of hand-foot-and-mouth disease in children with ev71 infection and the related factors.hand-foot-and-mouth disease (hfmd) is a common pediatric infectious disease caused by a variety of intestinal viruses. enterovirus 71 (ev71) is the primary pathogen that might cause severe symptoms and even death in children with hfmd. this study aimed to investigate the intestinal detoxification time of hfmd children with ev71 infection and its related factors.201526454441
systematic review of economic evaluations of vaccination programs in mainland china: are they sufficient to inform decision making?the purpose of the study was to systematically review economic evaluations of vaccine programs conducted in mainland china. we searched for economic evaluations of vaccination in china published prior to august 3, 2015 in eight english-language and three chinese-language databases. each article was appraised against the 19-item consensus on health economic criteria list (chec-list). we found 23 papers evaluating vaccines against hepatitis b (8 articles), streptococcus pneumoniae (5 articles), hu ...201526435189
the suramin derivative nf449 interacts with the 5-fold vertex of the enterovirus a71 capsid to prevent virus attachment to psgl-1 and heparan sulfate.nf449, a sulfated compound derived from the antiparasitic drug suramin, was previously reported to inhibit infection by enterovirus a71 (ev-a71). in the current work, we found that nf449 inhibits virus attachment to target cells, and specifically blocks virus interaction with two identified receptors--the p-selectin ligand, psgl-1, and heparan sulfate glycosaminoglycan--with no effect on virus binding to a third receptor, the scavenger receptor scarb2. we also examined a number of commercially a ...201526430888
a bivalent virus-like particle based vaccine induces a balanced antibody response against both enterovirus 71 and norovirus in mice.noroviruses are the main cause of severe viral gastroenteritis, which results in estimated 200,000 deaths each year, primarily in children in the developing world. genogroup ii.4 (gii.4) strains are responsible for the majority of norovirus outbreaks. enterovirus 71 (ev71), the leading causative agent of hand, foot and mouth disease, has recently been prevalent in asia-pacific regions, resulting in significant morbidity and mortality in young children. however, no vaccine is commercially availab ...201526424606
similar protective immunity induced by an inactivated enterovirus 71 (ev71) vaccine in neonatal rhesus macaques and children.during the development of enterovirus 71 (ev71) inactivated vaccine for preventing human hand, foot and mouth diseases (hfmd) by ev71 infection, an effective animal model is presumed to be significant and necessary. our previous study demonstrated that the vesicles in oral regions and limbs potentially associated with viremia, which are the typical manifestations of hfmd, and remarkable pathologic changes were identified in various tissues of neonatal rhesus macaque during ev71 infection. althou ...201526419198
antibodies to p-selectin glycoprotein ligand-1 block dendritic cell-mediated enterovirus 71 transmission and prevent virus-induced cells death.p-selectin glycoprotein ligand-1 (psgl-1) has been proved to serve as the functional receptor for enterovirus 71 (ev71). we found the abundant expression of psgl-1 on monocyte-derived dendritic cells (mddcs). however, we have previously demonstrated that mddcs did not support efficient replication of ev71. dendritic cells (dcs) have been described to be subverted by various viruses including ev71 for viral dissemination, we thus explore the potential contribution of psgl-1 on dc-mediated ev71 tr ...201526399965
enterovirus 71 infection caused neuronal cell death and cytokine expression in cultured rat neural cells.fatal enterovirus type-71 (ev71) cases are associated with central nervous system infection characterized by inflammatory cell infiltration and activation, cytokine overproduction, and neuronal cell death. although ev71 antigen has been detected in neurons and glia, the molecular mechanisms underlying ev71-associated neuroinflammation and neuronal cell death are not fully understood. using cultured rodent neural cell models, we found that ev71 infection preferentially caused cell death in neuron ...201526399559
enterovirus 71 2c protein inhibits nf-κb activation by binding to rela(p65).viruses evolve multiple ways to interfere with nf-κb signaling, a key regulator of innate and adaptive immunity. enterovirus 71 (ev71) is one of primary pathogens that cause hand-foot-mouth disease. here, we identify rela(p65) as a novel binding partner for ev71 2c protein from yeast two-hybrid screen. by interaction with ipt domain of p65, 2c reduces the formation of heterodimer p65/p50, the predominant form of nf-κb. we also show that picornavirus 2c family proteins inhibit nf-κb activation an ...201526394554
immunity and clinical efficacy of an inactivated enterovirus 71 vaccine in healthy chinese children: a report of further observations.to investigate the long-term effects on immunity of an inactivated enterovirus 71 (ev71) vaccine and its protective efficacy.201526381232
anti-enterovirus 71 agents of natural products.this review, with 42 references, presents the fascinating area of anti-enterovirus 71 natural products over the last three decades for the first time. it covers literature published from 2005-2015 and refers to compounds isolated from biogenic sources. in total, 58 naturally-occurring anti-ev71 compounds are recorded.201526370955
seroprevalence of enterovirus 71 antibody among children in china: a systematic review and meta-analysis.hand, foot and mouth disease mostly affects children and carries a substantial disease burden in the western pacific region. enterovirus 71 (ev71) is the most virulent causative agent, and a monovalent vaccine against ev71 will soon become commercially available in china. an improved understanding of ev71 epidemiology would aid policy decisions regarding childhood immunization in china. we aimed to assess and summarize information to date from individual seroepidemiologic studies of ev71 in main ...201526368058
tia-1 and tiar interact with 5'-utr of enterovirus 71 genome and facilitate viral replication.enterovirus 71 is one of the major causative pathogens of hfmd in children. upon infection, the viral rna is translated in an ires-dependent manner and requires several host factors for effective replication. here, we found that t-cell-restricted intracellular antigen 1 (tia-1), and tia-1 related protein (tiar) were translocated from nucleus to cytoplasm after ev71 infection and localized to the sites of viral replication. we found that tia-1 and tiar can facilitate ev71 replication by enhancing ...201526363455
development of a specific latex agglutination test to detect antibodies of enterovirus 71.a latex agglutination test (lat) was developed for the rapid detection of antibodies against the vp1 or vp1 proteins of enterovirus 71 (ev71). the proteins of interest including prokaryotically expressed vp1 and two strains of anti-vp1 monoclonal antibody (mcab) against ev71 were covalently linked to carboxylated latex using ethyl-dimethyl-amino-propyl carbodiimide (edc) to prepare sensitized latex beads. lat was evaluated by an enzyme-linked immunosorbent assay (elisa) as a reference test. the ...201526363276
a severe case of co-infection with enterovirus 71 and vaccine-derived poliovirus type ii.enterovirus 71 (ev71) is often identified as the primary pathogen that directly leads to severe cases of hfmd, whereas the association between other enteroviruses and ev71 infection remains largely unclear. here we report a rare case of a 5-year-old boy co-infected with ev71 and vaccine-derived poliovirus (vdpv) type ii, which were identified based on pcr and sequence analysis results and clinical symptoms and were characterized on ct. we determined that the ev71 strain belongs to the c4 subtype ...201526361010
global quantitative proteomic analysis of human glioma cells profiled host protein expression in response to enterovirus type 71 infection.enterovirus 71 (ev71) is one of the leading causes of hand, foot and mouth disease with neurological complications in some cases. to study the pathogenesis of ev71 infection, large-scale analyses of ev71 infected cells have been performed. however, most of these studies employed rhabdomyosarcoma (rd) cells or used transcriptomic strategy. here, we performed silac-based quantitative proteomic analysis of ev71-infected u251 cells, a human glioma cell line. a total of 3125 host proteins were quanti ...201526350028
co-infection of enterovirus 71 and staphylococcus aureus in a 6-month-old male infant. 201526322107
analysis of ev71 infection progression using triple-silac-based proteomics approach.enterovirus 71 (ev71), a member of picornaviridae, causes severe neurological and systemic illness in children. to better understand the virus-host cell interactions, we performed a triple-silac-based quantitative proteomics study monitoring host cell proteome changes after ev71 infection. based on the quantitative data for more than 4100 proteins, ∼17% of the proteins were found as significantly changed (p<0.01) at either 8 or 20 hours post infection. five biological processes and seven protein ...201526306425
association of chemotactic chemokine ligand 5 polymorphisms with the risk of developing severe enterovirus 71 infection.respiratory damage is a main manifestation of severe enterovirus 71 (ev71) infection. polymorphisms of -403g/a (rs2107538), -28c/g (rs2280788), and in1.1t/c (rs2280789) in chemotactic chemokine ligand 5 (ccl5) have linked with many respiratory diseases. in this study, we explored the possible correlation of ccl5 polymorphisms with severe ev71 infection. blood samples were obtained from 87 children hospitalized for ev71 infection. fifty-seven healthy children were enrolled as asymptomatic control ...201526304916
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