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[molecular epidemiology of hfmd-associated pathogen coxsackievirus a6 in fujian province, 2011-2013].in order to characterize the molecular epidemiology of hfmd-associated coxsackievirus a6 (cva6) in fujian province, a total of 1340 specimens from non-ev71 non-cva16 hfmd patients were collected during 2011-2013. isolated virus strains were identified and subtyped. full-length coding regions for the vp1 gene of the predominant serotype cva6 isolates were amplified and sequenced. among the 375 non-ev71 non-cva16 hfmd cases confirmed by virus isolation and molecular subtyping, 182 (48.5%) were fou ...201425868276
a virus-like particle based bivalent vaccine confers dual protection against enterovirus 71 and coxsackievirus a16 infections in mice.enterovirus 71(ev71) and coxsackievirus a16 (ca16) are responsible for hand, foot and mouth disease which has been prevalent in asia-pacific regions, causing significant morbidity and mortality in young children. co-circulation of and co-infection by both viruses underscores the importance and urgency of developing vaccines against both viruses simultaneously. here we report the immunogenicity and protective efficacy of a bivalent combination vaccine comprised of ev71 and ca16 virus-like particl ...201424950363
correlation analysis of ev71 detection and case severity in hand, foot, and mouth disease in the hunan province of china.an increase in the incidence of hand, foot and mouth disease (hfmd) cases has been observed in the hunan province of mainland china since 2009 with a particularly higher level of severe cases in 2010-2012. intestinal viruses of the picornaviridae family are responsible for the human syndrome associated with hfmd with enterovirus 71 (ev71) and coxsackievirus a16 (cox a16) being the most common causative strains. hfmd cases associated with ev71 are generally more severe with an increased associati ...201424941257
detection and characterization of viruses causing hand, foot and mouth disease from children in seri kembangan, malaysia.hand, foot and mouth disease (hfmd) is a common viral infection among infants and children. the major causative agents of hfmd are enterovirus 71 (ev71) and coxsackievirus a16 (cva16). recently, coxsackievirus a6 (cva6) infections were reported in neighboring countries. infected infants and children may present with fever, mouth/throat ulcers, rashes and vesicles on hands and feet. moreover, ev71 infections might cause fatal neurological complications. since 1997, ev71 caused fatalities in saraw ...201425776590
evaluation of monovalent and bivalent vaccines against lethal enterovirus 71 and coxsackievirus a16 infection in newborn mice.enterovirus 71 (ev71) and coxsackievirus a16 (cva16) have caused severe epidemics of hand, foot and mouth disease (hfmd) in the asia pacific in recent years, particularly in infants and young children. this disease has become a serious public health problem, as no vaccines or antiviral drugs have been approved for ev71 and ca16 infections. in this study, we compared four monovalent vaccines, including formalin-inactivated ev71 virus (iev71), ev71 virus-like particles (vlps) (vev71), formalin-ina ...201425483672
[research advances in molecular epidemiology and vaccines of coxsackievirus a16].epidemics of hand, foot and mouth disease (hfmd) have mainly been caused by coxsackievirus a16 (cva16) and enterovirus a 71 (ev-a71), which circulated alternatively or together in the affected area. cva16 has caused numerous outbreaks and epidemics in multiple countries and geographical regions, and has become an important public health problem. based on an analysis of the complete vp1 coding region, all cva16 strains can be divided into genotypes a, b1, and b2. furthermore, genotype b1 can be d ...201425272607
the role of enterovirus 71 and coxsackievirus a strains in a large outbreak of hand, foot, and mouth disease in 2012 in changsha, china.during 2012, changsha experienced a large outbreak of hand, foot, and mouth disease (hfmd), resulting in 25,438 cases, including 42 severe cases and eight deaths.201425236389
er stress, autophagy, and rna viruses.endoplasmic reticulum (er) stress is a general term for representing the pathway by which various stimuli affect er functions. er stress induces the evolutionarily conserved signaling pathways, called the unfolded protein response (upr), which compromises the stimulus and then determines whether the cell survives or dies. in recent years, ongoing research has suggested that these pathways may be linked to the autophagic response, which plays a key role in the cell's response to various stressors ...201425140166
protease 2a induces stress granule formation during coxsackievirus b3 and enterovirus 71 infections.stress granules (sgs) are granular aggregates in the cytoplasm that are formed under a variety of stress situations including viral infection. previous studies indicate that poliovirus, a member of picornaviridae, can induce sg formation. however, the exact mechanism by which the picornaviruses induce sg formation is unknown.201425410318
[sequence analysis of vp1 region of coxsackievirus a4 and coxsackievirus a10 in guangzhou city, 2010-2012].to identify the enterovirus from stool samples of patients with hand, foot and mouth disease(hfmd) in guangzhou from 2010 to 2012 and to perform phylogenetic analysis of the vp1 gene sequences of coxsackievirus a4 and coxsackievirus a10.201425219430
[serotype distribution of non-polio enterovirus in patients with acute flaccid paralysis during 2011-2012 in hebei province, china].this study aims to investigate the serotype distribution of non-polio enterovirus (npev) isolated from patients with acute flaccid paralysis (afp) during 2011-2012 in hebei province, china and to analyze the relationship between these viruses and afp. npev strains were isolated from the stool specimens from afp cases in hebei using human rhabdomyosarcoma cells (rd) and the mouse cell line expressing the gene for the human cellular receptor for poliovirus (l20b) according to the who requirements. ...201424772895
development of loop-mediated isothermal amplification (lamp) for universal detection of enteroviruses.enteroviruses are found in most environments and cause several diseases in humans. loop-mediated isothermal amplification (lamp) was adapted and evaluated for the rapid detection of enteroviruses. based on the highly conserved 5' untranslated region (5'-utr) of the human enteroviruses (hevs), particularly human enterovirus a (hev-a) and hev-b, a set of universal primers was designed. the lamp amplification was carried out under isothermal conditions at 61 °c, depending on the template concentrat ...201424426171
recombination strategies and evolutionary dynamics of the human enterovirus a global gene pool.we analysed natural recombination in 79 human enterovirus a strains representing 13 serotypes by sequencing of vp1, 2c and 3d genome regions. the half-life of a non-recombinant tree node in coxsackieviruses 2, 4 and 10 was only 3.5 years, and never more than 9 years. all coxsackieviruses that differed by more than 7 % of the nucleotide sequence in any genome region were recombinants relative to each other. enterovirus 71 (ev71), on the contrary, displayed remarkable genetic stability. three majo ...201424425417
[epidemiological features and pathogenic characteristics of hand, foot and mouth disease in gansu province, china during 2008-2012].this study aims to analyze the epidemiological features and pathogenic characteristics of hand, foot and mouth disease (hfmd) in gansu province, china and to provide a basis for the development of effective prevention and control measures. the descriptive epidemiological analysis was used to analyse the data of hfmd cases in gansu. the specimens collected from hospitals were subjected to rt-pcr or real-time pcr to detect human enterovirus (hev) nucleic acid, and hev strains were isolated using h ...201424772894
new coxsackievirus b4 genotype circulating in inner mongolia autonomous region, china.hand, foot, and mouth disease (hfmd) surveillance was initiated in the inner mongolia autonomous region of china in 2007, a crucial scrutiny for monitoring the prevalence of enterovirus serotypes associated with hfmd patients. however, this surveillance mostly focused on enterovirus 71 (ev-a71) and coxsackievirus a16; therefore, information on other enterovirus serotypes is limited. to identify the other circulating enterovirus serotypes in the hfmd outbreaks in inner mongolia in 2010, clinical ...201424595311
differential interferon pathway gene expression patterns in rhabdomyosarcoma cells during enterovirus 71 or coxsackievirus a16 infection.exposure of cells to type i interferon (ifn) induces an antiviral state that prevents viral infection, but viruses can utilize multiple tactics to antagonize the host immune system. enterovirus 71 (ev71) and coxsackievirus a16 (cva16) are two major pathogens that cause hand, foot, and mouth disease (hfmd), which is prevalent among children. we found that both ev71 and ca16 have different reactions to type i ifn pretreatment and induction patterns of type i ifn on rhabdomyosarcoma (rd) cells. fur ...201424735544
coxsackievirus a6 and enterovirus 71 causing hand, foot and mouth disease in cuba, 2011-2013.hand, foot and mouth disease (hfmd) is usually caused by coxsackievirus a16 or enterovirus 71 (ev71). between 2011 and 2013, hfmd cases were reported from different cuban provinces. a total of 42 clinical specimens were obtained from 23 patients. detection, identification and phylogenetic analysis of enterovirus-associated hfmd were carried out by virus isolation, specific enterovirus pcr and partial vp1 sequences. hev was detected in 11 hfmd cases. emerging genetic variants of coxsackievirus a6 ...201424719197
molecular epidemiology of enterovirus 71, coxsackievirus a16 and a6 associated with hand, foot and mouth disease in spain.hand, foot and mouth disease (hfmd) is a childhood illness frequently caused by genotypes belonging to the enterovirus a species, including coxsackievirus (cv)-a16 and enterovirus (ev)-71. between 2010 and 2012, several outbreaks and sporadic cases of hfmd occurred in different regions of spain. the objective of the present study was to describe the enterovirus epidemiology associated with hfmd in the country. a total of 80 patients with hfmd or atypical rash were included. detection and typing ...201424033818
enterovirus infection in children attending two outpatient clinics in zhejiang province, china.enteroviruses are responsible for hand, foot, and mouth disease, and have caused many deaths in china during recent years. but the natural history of enterovirus infection in children, especially asymptomatic children, is not yet clear. from april 2011 to may 2012, 505 stool and throat swab samples of children attending outpatients clinics in two hospitals were collected weekly to test for enterovirus 71, coxsackievirus a16, and other enterovirus nucleic acids by real-time rt-pcr. two hundred si ...201424519430
dermatological spectrum of hand, foot and mouth disease from classical to generalized exanthema.hand, foot and mouth disease (hfmd) is classically defined as a childhood fever accompanied by a rash with vesicles or erosions of the oral mucosa, hands, feet and sometimes the buttocks. severe neurological complications are associated with enterovirus 71 outbreaks in asia. recently, it has been suggested that hfmd is related to coxsackie virus a6 (cv-a6) when there is an atypical rash. the objective of the study is to determine the dermatological pattern of hfmd and to identify the virus serot ...201424463804
coxsackievirus a16: epidemiology, diagnosis, and vaccine.coxsackievirus 16 (ca16) is one of the major pathogens associated with hand, foot, and mouth disease (hfmd) in infants and young children. in recent years, ca16 and human enterovirus 71 (ev71) have often circulated alternatively or together in the western pacific region, which has become an important public health problem in this region. hfmd caused by ca16 infection is generally thought to be mild and self-limiting. however, recently several severe and fatal cases involving ca16 have been repor ...201424231751
co-circulation and genomic recombination of coxsackievirus a16 and enterovirus 71 during a large outbreak of hand, foot, and mouth disease in central china.a total of 1844 patients with hand, foot, and mouth disease (hfmd), most of them were children of age 1-3-year-old, in central china were hospitalized from 2011 to 2012. among them, 422 were infected with coxsackievirus a16 (cva16), 334 were infected with enterovirus 71 (ev71), 38 were co-infected with ev71 and cva16, and 35 were infected with other enteroviruses. molecular epidemiology analysis revealed that ev71 and cva16 were detected year-round, but ev71 circulated mainly in july and cva16 c ...201424776922
inhibition of enterovirus 71 infection by antisense octaguanidinium dendrimer-conjugated morpholino oligomers.enterovirus 71 (ev-71) infections are generally manifested as mild hand, foot and mouth disease, but have been reported to cause severe neurological complications with high mortality rates. treatment options remain limited due to the lack of antivirals. octaguanidinium-conjugated morpholino oligomers (vivo-mos) are single-stranded dna-like antisense agents that can readily penetrate cells and reduce gene expression by steric blocking of complementary rna sequences. in this study, inhibitory effe ...201424769243
prospect and challenges for the development of multivalent vaccines against hand, foot and mouth diseases.enterovirus 71 (ev71), an emerging neurotropic virus and coxsackieviruses (cv) are the major causative agents of hand, foot and mouth diseases (hfmd). these viruses have become a serious public health threat in the asia pacific region. formalin-inactivated ev71 (fi-ev71) vaccines have been developed, evaluated in human clinical trials and were found to elicit full protection against ev71. their failure to prevent cva16 infections could compromise the acceptability of monovalent ev71 vaccines. bi ...201425218294
prevalence of multiple enteroviruses associated with hand, foot, and mouth disease in shijiazhuang city, hebei province, china: outbreaks of coxsackieviruses a10 and b3.hand, foot, and mouth disease (hfmd) has been one of the most common infectious diseases in shijiazhuang city, as is the situation in china overall. in the national hfmd surveillance system, the pathogen detection was focused on ev-a71 and cva16, and therefore, information on the other evs is very limited. in order to identify the circulating ev serotypes in the hfmd outbreaks in shijiazhuang city during 2010-2012, 4045 patients presented with hfmd were recruited in the study, and clinical sampl ...201424392117
a combination vaccine comprising of inactivated enterovirus 71 and coxsackievirus a16 elicits balanced protective immunity against both viruses.enterovirus 71 (ev71) and coxsackievirus a16 (ca16) are the two major causative agents of hand, foot and mouth disease (hfmd), which is an infectious disease frequently occurring in children. a bivalent vaccine against both ev71 and ca16 is highly desirable. in the present study, we compare monovalent inactivated ev71, monovalent inactivated ca16, and a combination vaccine candidate comprising of both inactivated ev71 and ca16, for their immunogenicity and in vivo protective efficacy. the two mo ...201424657161
improved detection limit in rapid detection of human enterovirus 71 and coxsackievirus a16 by a novel reverse transcription-isothermal multiple-self-matching-initiated amplification assay.rapid detection of human enterovirus 71 (ev71) and coxsackievirus a16 (cva16) is important in the early phase of hand-foot-and-mouth disease (hfmd). in this study, we developed and evaluated a novel reverse transcription-isothermal multiple-self-matching-initiated amplification (rt-imsa) assay for the rapid detection of ev71 and cva16 by use of reverse transcriptase, together with a strand displacement dna polymerase. real-time rt-imsa assays using a turbidimeter and visual rt-imsa assays to det ...201424648558
changing aetiology of hand, foot and mouth disease in linyi, china, 2009-2011.millions of hand, foot and mouth disease cases occur annually and the disease is considered a significant public health threat in china. we have focused on linyi for 3 years to analyse the aetiological spectrum and epidemic changes. the reported number of cases of hfmd in linyi declined in 2011,with the percentage of hev71 dropping to 11%. although cva16 rose to 51% in 2011, the number of cva16 cases did not change significantly compared with the previous 2 years. other types of enteroviruses we ...201423910234
development of a sandwich elisa for the quantification of enterovirus 71.since 2008, enterovirus 71 (ev71) has been responsible for high-mortality seasonal epidemics of hand, foot and mouth disease in china. currently many groups in the world are in the process of developing ev71 vaccines to combat this deadly disease. we have developed three ev71-specific monoclonal antibodies, and in this study we report the establishment of a fast and cost-effective sandwich elisa kit for measurement of virus concentration in ev71 vaccines using a pair of mouse anti-ev71 monoclona ...201423728855
[hand, foot and mouth disease--more than a harmless "childhood disease"].hand, foot and mouth disease (hfmd) is a highly contagious, world-wide distributed viral illness that affects predominantly children. it is caused by several enteroviruses, such as coxsackieviruses a6, a10, a16 and enterovirus 71. in most cases, hfmd follows a benign and self-limiting course. after an incubation period of 3 to 10 days, fever and sore throat, the first symptoms of the disease, appear. a few days later, maculopapular or vesicular eruptions form on the palms and soles as well as in ...201424490433
cryo-electron microscopy study of insect cell-expressed enterovirus 71 and coxsackievirus a16 virus-like particles provides a structural basis for vaccine development.enterovirus 71 (ev71) and coxsackievirus a16 (ca16) are the two most common etiological agents responsible for the epidemics of hand, foot, and mouth disease (hfmd), a childhood illness with occasional severe neurological complications. a number of vaccine candidates against ev71 or ca16 have been reported; however, no vaccine is currently available for clinical use. here, we generated a secreted version of ev71 and ca16 virus-like particles (vlps) using a baculovirus-insect cell expression syst ...201424672036
emergence of enterovirus 71 c4a in denmark, 2009 to 2013.enterovirus (ev) 71 has emerged as a primary cause of severe neurologic enterovirus infection in the aftermath of the global polio eradication effort. eleven subgenotypes of ev71 exist, the c4 subgenotype being associated with large outbreaks in asia with high mortality rates. this subgenotype has rarely been reported in europe. in the period between 1 january 2009 and 31 december 2013 a total of 1,447 ev positive samples from 1,143 individuals were sent to the statens serum institute (ssi), and ...201425306878
coxsackievirus a6 associated hand, foot and mouth disease in adults: clinical presentation and review of the literature.hand, foot, and mouth disease (hfmd) is generally considered a rare illness in adults. classically, hfmd has been strongly associated with coxsackievirus strain a16 and enterovirus 71. the coxsackievirus a6 (cva6) strain has been linked to severe worldwide outbreaks since 2008. cva6 is associated with a more severe and profound course of disease, affecting both children and adults.201424932735
combined approaches to flexible fitting and assessment in virus capsids undergoing conformational change.fitting of atomic components into electron cryo-microscopy (cryoem) density maps is routinely used to understand the structure and function of macromolecular machines. many fitting methods have been developed, but a standard protocol for successful fitting and assessment of fitted models has yet to be agreed upon among the experts in the field. here, we created and tested a protocol that highlights important issues related to homology modelling, density map segmentation, rigid and flexible fitti ...201424333899
[genetic evidence for recombination and mutation in the emergence of human enterovirus 71].we wished to understand the genetic recombination and phylogenetic characteristics of human en- terovirus a71 (ev-a71) and to explore its potential virulence-related sites. full-length genomes of three ev-a71 strains isolated from patients in chenzhou city (china) were sequenced and analyzed. possible re- combination events and crossover sites were analyzed with recombination detection program v4. 1. 6 by comparison with the complete genome sequences of 231 strains of ev-a71. similarly, plot and ...201425562969
prevalence and characterization of enterovirus infections among pediatric patients with hand foot mouth disease, herpangina and influenza like illness in thailand, 2012.hand, foot, and mouth disease (hfmd) and herpangina are common infectious diseases caused by several genotypes of human enterovirus species a and frequently occurring in young children. this study was aimed at analyzing enteroviruses from patients with these diseases in thailand in 2012. detection and genotype determination of enteroviruses were accomplished by reverse transcription-polymerase chain reaction and sequencing of the vp1 region. enterovirus-positive samples were differentiated into ...201424887237
induction and suppression of innate antiviral responses by picornaviruses.the family picornaviridae comprises of small, non-enveloped, positive-strand rna viruses and contains many human and animal pathogens including enteroviruses (e.g. poliovirus, coxsackievirus, enterovirus 71 and rhinovirus), cardioviruses (e.g. encephalomyocarditis virus), hepatitis a virus and foot-and-mouth disease virus. picornavirus infections activate a cytosolic rna sensor, mda5, which in turn, induces a type i interferon response, a crucial component of antiviral immunity. moreover, picorn ...201425086453
antiviral activity of ginsenosides against coxsackievirus b3, enterovirus 71, and human rhinovirus 3.ginsenosides are the major components responsible for the biochemical and pharmacological actions of ginseng, and have been shown to have various biological activities. in this study, we investigated the antiviral activities of seven ginsenosides [protopanaxatriol (pt) type: re, rf, and rg2; protopanaxadiol (pd) type: rb1, rb2, rc, and rd)] against coxsackievirus b3 (cvb3), enterovirus 71 (ev71), and human rhinovirus 3 (hrv3).201425378991
auf1 is recruited to the stress granules induced by coxsackievirus b3.stress granules (sgs) are cytoplasmic granules that are formed in cells when stress occurs. in this study, we found that sgs formed in cells infected with coxsackievirus b3 (cvb3), evidenced with the co-localization of some accepted sg markers in the viral infection-induced granules. we further discovered that adenosine-uridine (au)-rich element rna binding factor 1 (auf1), which can bind to mrnas and regulate their translation, was recruited to the sgs in response to high dose of cvb3 by detect ...201425148713
binding of glutathione to enterovirus capsids is essential for virion morphogenesis.enteroviruses (family of the picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. we report the discovery of tp219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. we show that tp219 binds directly glutathione (gsh), thereby r ...201424722756
coxsackievirus cloverleaf rna containing a 5' triphosphate triggers an antiviral response via rig-i activation.upon viral infections, pattern recognition receptors (prrs) recognize pathogen-associated molecular patterns (pamps) and stimulate an antiviral state associated with the production of type i interferons (ifns) and inflammatory markers. type i ifns play crucial roles in innate antiviral responses by inducing expression of interferon-stimulated genes and by activating components of the adaptive immune system. although pegylated ifns have been used to treat hepatitis b and c virus infections for de ...201424759703
antiviral activity of lanatoside c against dengue virus infection.dengue infection poses a serious threat globally due to its recent rapid spread and rise in incidence. currently, there is no approved vaccine or effective antiviral drug for dengue virus infection. in response to the urgent need for the development of an effective antiviral for dengue virus, the us drug collection library was screened in this study to identify compounds with anti-dengue activities. lanatoside c, an fda approved cardiac glycoside was identified as a candidate anti-dengue compoun ...201425251726
coxsackievirus a 16 infection does not interfere with the specific immune response induced by an enterovirus 71 inactivated vaccine in rhesus monkeys.hand, foot and mouth disease is usually caused by enterovirus 71 (ev71) and coxsackievirus a 16 (ca16), which are members of the picornaviridae family. in the present study, the characteristics of the immune response induced by an ev71 inactivated vaccine (made from human diploid cells) were explored in the presence of ca16 infection, based on the previously established neonatal rhesus monkey model. the typical clinical manifestations, including body temperature, viral viremia and virus shedding ...201424958699
tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in ev71 encephalomyelitis.enterovirus 71 (ev71; family picornaviridae, species human enterovirus a) usually causes hand, foot, and mouth disease, which may rarely be complicated by fatal encephalomyelitis. we investigated extra-central nervous system (extra-cns) tissues capable of supporting ev71 infection and replication, and have correlated tissue infection with expression of putative viral entry receptors, scavenger receptor b2 (scarb2), and p-selectin glycoprotein ligand-1 (psgl-1). formalin-fixed, paraffin-embedded ...201424378407
immunogenicity, safety, and immune persistence of a novel inactivated human enterovirus 71 vaccine: a phase ii, randomized, double-blind, placebo-controlled trial.vaccination is considered a top priority for the control of human enterovirus 71 (ev71) infection outbreaks.201423922377
enterovirus 71 pathogenicity in monkeys and cotton rats.enterovirus 71 (ev71) is a neurovirulent non-polio enterovirus that can cause severe central nervous system (cns) infection in infants. vervet monkeys infected intracerebrally or intramuscularly with ev71 isolates from the bulgarian outbreak of 1975 developed clinical manifestations and pathological signs of encephalomyelitis and spinal poliomyelitis that were similar to ev71 neuroinfection in children. in addition, vervet monkeys with encephalomyelitis had severe alterations in the choroid plex ...201424158347
the population-based health effect of hand, foot and mouth disease in children in shanghai.an effective enterovirus 71 (ev71) vaccine is needed to control the annual outbreaks of hand, foot and mouth disease (hfmd) in china. adequate epidemiologic data relating to hfmd are needed to make decisions about appropriate public health interventions and implementation of the new ev71 vaccine.201424153009
a novel finding for enterovirus virulence from the capsid protein vp1 of ev71 circulating in mainland china.enterovirus 71 (ev71) is a neurotropic virus that causes various clinical manifestations in young children, ranging from asymptomatic to fatal. different pathotypes of ev71 notably differ in virulence. several virulence determinants of ev71 have been predicted. however, these reported virulence determinants could not be used to identify the ev71 strains of subgenotype c4, which mainly circulate in china. in this study, vp1 sequences of 37 ev71 strains from severe cases (sc-ev71) and 192 ev71 str ...201424442718
interleukin-8 is elevated in severe hand, foot, and mouth disease.enterovirus 71 (ev71) infections can cause hand, foot, and mouth disease (hfmd), which is a potentially fatal illness in children. epidemics of hfmd are seen every year globally and present an increasing threat to public health worldwide.201424423718
spatio-temporal analysis on enterovirus cases through integrated surveillance in taiwan.severe epidemics of enterovirus have occurred frequently in malaysia, singapore, taiwan, cambodia, and china, involving cases of pulmonary edema, hemorrhage and encephalitis, and an effective vaccine has not been available. the specific aim of this study was to understand the epidemiological characteristics of mild and severe enterovirus cases through integrated surveillance data.201424400725
the gene expression profile of peripheral blood mononuclear cells from ev71-infected rhesus infants and the significance in viral pathogenesis.enterovirus 71 (ev71) is the major pathogen responsible for fatal hand, foot and mouth disease (hfmd). our previous work reported on an ev71-infected rhesus monkey infant model that presented with histo-pathologic changes of the central nervous system (cns) and lungs. this study is focused on the correlated modulation of gene expression in the peripheral blood mononuclear cells (pbmcs) from ev71-infected rhesus monkey infants. the expression of more than 500 functional genes associated with mult ...201424392094
chimeric virus-like particle vaccines displaying conserved enterovirus 71 epitopes elicit protective neutralizing antibodies in mice through divergent mechanisms.enterovirus 71 (ev71) is a major causative agent of hand, food, and mouth disease, which frequently occurs in young children. since there are 11 subgenotypes (a, b1 to b5, and c1 to c5) within ev71, an ev71 vaccine capable of protecting against all of these subgenotypes is desirable. we report here the vaccine potential and protective mechanism of two chimeric virus-like particles (vlps) presenting conserved neutralizing epitopes of ev71. we show that fusions of hepatitis b core antigen (hbc) wi ...201424131712
the nuclear protein sam68 is redistributed to the cytoplasm and is involved in pi3k/akt activation during ev71 infection.nuclear proteins can be triggered to be redistributed to the cytoplasm to assist with ev71 virus replication. this process is frequently involved in cellular signal transduction upon virus infection. in this study, we have demonstrated that a new nuclear protein, 68-kda src-associated in mitosis protein (sam68), was translocated to the cytoplasm and was co-localized with ev71 during virus infection. confocal microscopy and subcellular fractionation assay confirmed that virus 3c protease triggere ...201424316008
peripheral t lymphocyte subset imbalances in children with enterovirus 71-induced hand, foot and mouth disease.inflammatory mediators (i.e. cytokines) play a pivotal role in the regulation of pathophysiological processes during ev71-induced hand, foot and mouth disease (hfmd). different t cell subsets have distinct cytokine secretion profiles, and alteration in the t cell subsets frequency (imbalance) during infection leads to changed cytokine patterns. however, the effects of ev71 infection on t cell subsets were not clear. the objective of this study was to determine whether ev71-induced hfmd can be ex ...201424316007
effect of all-trans-retinoic acid on enterovirus 71 infection in vitro.our previous studies have shown that vitamin a (va) status is associated with antiviral immunity and pathogenic conditions in enterovirus 71 (ev71)-infected children. in the present study, we established an in vitro model to investigate the effects and potential mechanism of the antiviral activity of va. human monocytic u937 cells were cultured in vitro and infected with ev71. all-trans-retinoic acid (atra), the active metabolite of va, and ro 41-5253, a retinoic acid receptor-α (rar-α) antagoni ...201424495389
polyc-binding protein 1 interacts with 5'-untranslated region of enterovirus 71 rna in membrane-associated complex to facilitate viral replication.enterovirus 71 (ev71) is one causative agent of hand, foot, and mouth disease (hfmd), which may lead to severe neurological disorders and mortality in children. ev71 genome is a positive single-stranded rna containing a single open reading frame (orf) flanked by 5'-untranslated region (5'utr) and 3'utr. the 5'utr is fundamentally important for virus replication by interacting with cellular proteins. here, we revealed that poly(c)-binding protein 1 (pcbp1) specifically binds to the 5'utr of ev71. ...201424489926
hand, foot, and mouth disease in china, 2008-12: an epidemiological study.hand, foot, and mouth disease is a common childhood illness caused by enteroviruses. increasingly, the disease has a substantial burden throughout east and southeast asia. to better inform vaccine and other interventions, we characterised the epidemiology of hand, foot, and mouth disease in china on the basis of enhanced surveillance.201424485991
neutralizing antibodies can initiate genome release from human enterovirus 71.antibodies were prepared by immunizing mice with empty, immature particles of human enterovirus 71 (ev71), a picornavirus that causes severe neurological disease in young children. the capsid structure of these empty particles is different from that of the mature virus and is similar to "a" particles encountered when picornaviruses recognize a potential host cell before genome release. the monoclonal antibody e18, generated by this immunization, induced a conformational change when incubated at ...201424469789
enterovirus 71 infection-associated acute flaccid paralysis: a case series of long-term neurologic follow-up.the authors undertook long-term neurologic outcomes of 27 patients aged 0 to 15 years with enterovirus 71-related acute flaccid paralysis from june 1998 to july 2012. motor function outcome was graded from class i (complete recovery) to class v (permanent paralytic limbs). twelve of 20 patients (60%) who received intravenous immunoglobulin for treatment of acute flaccid paralysis had motor function outcomes in classes iii to v. the median duration of follow-up was 6 months, during which time 7 o ...201424453152
development and evaluation of a real-time method of simultaneous amplification and testing of enterovirus 71 incorporating a rna internal control system.human enterovirus 71 (ev71) is a primary etiological agent of hand, foot, and mouth disease (hfmd). the associated infections have posed a serious threat to the public health. in the present study, a real-time simultaneous amplification and testing (sat) technology was developed for detecting ev71 (sat-ev71). the rna of ev71 and an internal control (ic) were amplified and analyzed simultaneously by isothermal amplification and real-time detection of fluorescence using routine real-time pcr. furt ...201424269796
clinico-radiological spectrum in enterovirus 71 infection involving the central nervous system in children.enterovirus 71 infection causes hand, foot and mouth disease in children, and can produce diverse neurologic complications. epidemics occurring in korea between 2009 and 2012 resulted in the death of some patients. the present study aimed to clarify the correlation between clinical features and mri findings in patients presenting with acute neurologic manifestations related to enterovirus 71 infection. based on their clinical features, the patients were classified into four clinical groups: (1) ...201424169271
dominant cd4-dependent rna-dependent rna polymerase-specific t-cell responses in children acutely infected with human enterovirus 71 and healthy adult controls.human enterovirus 71 (ev71) is one of the major causes of hand, foot and mouth disease (hfmd), which leads to significant mortality in infected children. a prophylactic vaccine is urgently needed. however, little is known about the protective t-cell immunity in individuals infected with the ev71 virus. in this study, we performed a comprehensive ex vivo interferon-γ elispot analysis in 31 children infected with ev71 as well as in 40 healthy adult controls of the cd4(+) and cd8(+) t-cell response ...201424329688
modification of picornavirus genomic rna using 'click' chemistry shows that unlinking of the vpg peptide is dispensable for translation and replication of the incoming viral rna.picornaviruses constitute a large group of viruses comprising medically and economically important pathogens such as poliovirus, coxsackievirus, rhinovirus, enterovirus 71 and foot-and-mouth disease virus. a unique characteristic of these viruses is the use of a viral peptide (vpg) as primer for viral rna synthesis. as a consequence, all newly formed viral rna molecules possess a covalently linked vpg peptide. it is known that vpg is enzymatically released from the incoming viral rna by a host p ...201424243841
more-powerful virus inhibitors from structure-based analysis of hev71 capsid-binding molecules.enterovirus 71 (hev71) epidemics in children and infants result mainly in mild symptoms; however, especially in the asia-pacific region, infection can be fatal. at present, no therapies are available. we have used structural analysis of the complete virus to guide the design of hev71 inhibitors. analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-hev71 activities pinpointed key structure-activity correlates. we then identified additional potentially bene ...201424509833
time series analysis of hand-foot-mouth disease hospitalization in zhengzhou: establishment of forecasting models using climate variables as predictors.large-scale outbreaks of hand-foot-mouth disease (hfmd) have occurred frequently and caused neurological sequelae in mainland china since 2008. prediction of the activity of hfmd epidemics a few weeks ahead is useful in taking preventive measures for efficient hfmd control.201424498221
construction and characterization of a recombinant human adenovirus type 3 vector containing two foreign neutralizing epitopes in hexon.the "antigen capsid-incorporation" strategy has been developed for adenovirus-based vaccines in the context of several diseases. exogenous antigenic peptides incorporated into the adenovirus capsid structure can induce a robust and boosted antigen-specific immune response. recently, we sought to generate a multivalent adenovirus type 3 (ad3) vaccine vector by incorporating multiple epitopes into the major adenovirus capsid protein, hexon. in the present study, a multivalent recombinant ad3 vacci ...201424518297
risk factors for critical disease and death from hand, foot and mouth disease.there has been a high mortality and morbidity rate of critical and fatal patients from hand, foot and mouth disease (hfmd) in china in recent. causes for development of critical and fatal disease remain unclear.201424577041
phylogenetic analysis of the vp1 gene of enterovirus 71 in guangzhou during the high occurrence period of 2008.an outbreak of hand, foot, and mouth disease (hfmd) in guangzhou in 2008 affected over 10,000 children and resulted in high hospital admission rates. to investigate the molecular epidemiological pattern of ev71 infections in guangzhou, throat swab samples were collected from 102 children clinically diagnosed with hfmd from may to july of 2008 in guangzhou. partial vp1 (virus protein 1) fragments of enterovirus 71 (ev71) isolates were sequenced, and used alongside ev71 sequences entered in genban ...201424515837
a 3c(pro)-dependent bioluminescence imaging assay for in vivo evaluation of anti-enterovirus 71 agents.enterovirus 71 (ev71), a member of picornaviridae, is one of the major pathogens of human hand, foot and mouth disease. ev71 mainly infects children and causes severe neurological complications and even death. the pathogenesis of ev71 infection is largely unknown, and no clinically approved vaccine or effective treatment is available to date. here we described a novel bioluminescence imaging approach for ev71 detection. in this approach, a plasmid-based reporter was constructed to express the fu ...201424263113
construction of an infectious cdna clone of enterovirus 71: insights into the factors ensuring experimental success.enterovirus 71 (ev 71) is a causative agent of mild hand foot and mouth disease but is capable of causing severe complications in the cns in young children. reverse genetics technology is currently widely used to study the pathogenesis of the virus. the aim of this work was to determine and evaluate the factors which can contribute to infectivity of ev 71 rna transcripts in vitro. two strategies, overlapping rt-pcr and long distance rt-pcr, were employed to obtain the full-length genome cdna clo ...201424361875
the mechanism of translation initiation on type 1 picornavirus iress.picornavirus type 1 iress comprise five principal domains (dii-dvi). whereas dv binds eif4g, a conserved aug in dvi was suggested to stimulate attachment of 43s ribosomal preinitiation complexes, which then scan to the initiation codon. initiation on type 1 iress also requires ires trans-acting factors (itafs), and several candidates have been proposed. here, we report the in vitro reconstitution of initiation on three type 1 iress: poliovirus (pv), enterovirus 71 (ev71), and bovine enterovirus ...201424357634
genetic polymorphism of ccl2-2518, cxcl10-201, il8+781 and susceptibility to severity of enterovirus-71 infection in a chinese population.the goal of this study was to examine the relationship between ccl2-2518a/g, cxcl10-201a/g, and il8+781c/t gene polymorphism and severity of enterovirus 71 (ev71) infection in a chinese population.201424609754
[seroepidemiology and molecular epidemiology of enterovirus type 71 in the world and the russian federation].a review of recent publications on epidemiology and seroepidemiology of enterovirus type 71 in various regions of the world and authors' own results of study of seroepidemiology and molecular epidemiology of ev71 in russia are presented.201424605685
cell and tissue tropism of enterovirus 71 and other enteroviruses infections.enterovirus 71 (ev71) is a member of picornaviridae that causes mild and self-limiting hand, foot, and mouth disease (hfmd). however, ev71 infections can progress to polio-like paralysis, neurogenic pulmonary edema, and fatal encephalitis in infants and young children. large ev71 outbreaks have been reported in taiwan, china, japan, malaysia, singapore, and australia. this virus is considered a critical emerging public health threat. ev71 is an important crucial neurotropic enterovirus for which ...201424602216
molecular comparison and evolutionary analyses of vp1 nucleotide sequences of new african human enterovirus 71 isolates reveal a wide genetic diversity.most circulating strains of human enterovirus 71 (ev-a71) have been classified primarily into three genogroups (a to c) on the basis of genetic divergence between the 1d gene, which encodes the vp1 capsid protein. the aim of the present study was to provide further insights into the diversity of the ev-a71 genogroups following the recent description of highly divergent isolates, in particular those from african countries, including madagascar. we classified recent ev-a71 isolates by a large comp ...201424598878
antiviral activity of hederasaponin b from hedera helix against enterovirus 71 subgenotypes c3 and c4a.enterovirus 71 (ev71) is the predominant cause of hand, foot and mouth disease (hfmd). the antiviral activity of hederasaponin b from hedera helix against ev71 subgenotypes c3 and c4a was evaluated in vero cells. in the current study, the antiviral activity of hederasaponin b against ev71 c3 and c4a was determined by cytopathic effect (cpe) reduction method and western blot assay. our results demonstrated that hederasaponin b and 30% ethanol extract of hedera helix containing hederasaponin b sho ...201424596620
an atypical winter outbreak of hand, foot, and mouth disease associated with human enterovirus 71, 2010.to analyze the epidemiological characteristics and pathogenic molecular characteristics of an hand, foot, and mouth disease (hfmd) outbreak caused by enterovirus 71 in linyi city, shandong province, china during november 30 to december 28, 2010.201424589030
comparative study of the immunogenicity in mice and monkeys of an inactivated ca16 vaccine made from a human diploid cell line.the coxsackie a16 virus (ca16), along with enterovirus 71 (ev71), is a primary pathogen that causes hand, foot, and mouth disease (hfmd). to control hfmd, ca16, and ev71 vaccines are needed. in this study, an experimental inactivated ca16 vaccine was prepared using human diploid cells, and the vaccine's immunogenicity was analyzed in mice and rhesus monkeys. the results showed that the neutralizing antibody was developed in a dose-dependent manner, and was sustained for 70 days with an average g ...201424583556
attenuation of human enterovirus 71 high-replication-fidelity variants in ag129 mice.in a screen for ribavirin resistance, a novel high-fidelity variant of human enterovirus 71 (ev71) with the single amino acid change l123f in its rna-dependent rna polymerase (rdrp or 3d) was identified. based on the crystal structure of ev71 rdrp, l123 locates at the entrance of the rna template binding channel, which might form a fidelity checkpoint. ev71 rdrp-l123f variants generated less progeny in a guanidine resistance assay and virus populations with lower mutation frequencies in cell cul ...201424623423
a polymorphism in melanoma differentiation-associated gene 5 may be a risk factor for enterovirus 71 infection.enterovirus 71 (ev71) infection has a wide variety of clinical manifestations, from no symptoms to fatal disease. host immune response may be a determinant of disease severity. we investigated the association of polymorphisms in three pattern recognition receptor (prr) genes-toll-like receptor 3 (tlr3) (rs3775291), retinoic acid-inducible gene i (rig-i) (rs10813831) and melanoma differentiation-associated gene 5 (mda5) (rs1990760)-with the severity of ev71 infection. polymorphisms of candidate g ...201424621100
development of enterovirus 71 vaccines: from the lab bench to phase iii clinical trials.the widespread epidemics of enterovirus 71 (ev71) seriously affected the western pacific region. young children, especially those younger than 3 years are the most susceptible population to the ev71-associated diseases. several asian countries have begun to focus on the research and development of ev71 vaccines. five inactivated whole-virus ev71 candidate vaccines (three were manufactured in mainland china based on a c4 genotype strain, one in taiwan based on a b4 genotype strain and one in sing ...201424621093
epidemiology and seroepidemiology of human enterovirus 71 among thai populations.human enterovirus 71 (ev71) is an important pathogen caused large outbreaks in asian-pacific region with severe neurological complications and may lead to death in young children. understanding of the etiological spectrum and epidemic changes of enterovirus and population's immunity against ev71 are crucial for the implementation of future therapeutic and prophylactic intervention.201424548776
overall codon usage pattern of enterovirus 71.hand, foot, and mouth disease (hfmd) is a systemic illness in children and is usually caused by enterovirus 71 (ev71). to provide new insights into the genetic features of ev71 and the relationship between the overall codon usage pattern of this virus and that of humans, values for relative synonymous codon usage (rscu), effective number of codons (enc), codon adaptation index (cai), and nucleotide composition were calculated and analyzed. the relationship between enc values and (g+c)₃% suggests ...201424535860
recent developments in antiviral agents against enterovirus 71 infection.enterovirus 71 (ev-71) is the main etiological agent of hand, foot and mouth disease (hfmd). recent ev-71 outbreaks in asia-pacific were not limited to mild hfmd, but were associated with severe neurological complications such as aseptic meningitis and brainstem encephalitis, which may lead to cardiopulmonary failure and death. the absence of licensed therapeutics for clinical use has intensified research into anti-ev-71 development. this review highlights the potential antiviral agents targetin ...201424521134
phenotypic and genotypic characteristics of novel mouse cell line (nih/3t3)-adapted human enterovirus 71 strains (ev71:tllm and ev71:tllmv).since its identification in 1969, enterovirus 71 (ev71) has been causing periodic outbreaks of infection in children worldwide and most prominently in the asia-pacific region. understanding the pathogenesis of enterovirus 71 (ev71) is hampered by the virus's inability to infect small animals and replicate in their derived in vitro cultured cells. this manuscript describes the phenotypic and genotypic characteristics of two selected ev71 strains (ev71:tllm and ev71:tllmv), which have been adapted ...201424671184
protection against lethal enterovirus 71 challenge in mice by a recombinant vaccine candidate containing a broadly cross-neutralizing epitope within the vp2 ef loop.human enterovirus 71 (ev71) is the main causative agent of hand, foot, and mouth disease (hfmd) and is associated with several severe neurological complications in the asia-pacific region. here, we evaluated that while passive transfer of neutralizing monoclonal antibody (nmab) against the vp2 protein protect against lethal ev71 infection in balb/c mice. protective nmab were mapped to residues 141-155 of vp2 by peptide elisa. high-resolution structural analysis showed that the epitope is part of ...201424669278
update of enterovirus 71 infection: epidemiology, pathogenesis and vaccine.enterovirus 71 (ev71) is a neurotropic human pathogen that is the causative agent of hand foot and mouth disease (hfmd), herpangina and brain stem encephalitis. recurrent ev71 epidemics of various scales have occurred in the asia-pacific region. several specific cell surface molecules serve as the receptors for ev71. identification of the receptors is an important step to understand ev71 disease. cytokines, lymphocytes and monocytes contribute significantly to ev71 pathogenesis. the interaction ...201424579906
the molecule of dc-sign captures enterovirus 71 and confers dendritic cell-mediated viral trans-infection.enterovirus 71 (ev71) is the main causative agent of hand, foot and mouth disease that occurs in young children. neither antiviral agents nor vaccines are available for efficiently combating viral infection. study of ev71-host interplay is important for understanding viral infection and developing strategies for prevention and therapy. here the interactions of ev71 with human dendritic cells were analyzed.201424620896
serum cytokine profiles of children with human enterovirus 71-associated hand, foot, and mouth disease.cytokine profiles may impact the pathogenicity and severity of hand, foot, and mouth disease caused by human enterovirus (hev) 71. in 91 severe or mild hev 71-associated hand, foot, and mouth disease children, serum was collected between days 2 and 10 or day >10. serum cytokines including type 1 t helper (th1) cytokines: interleukin (il)-2, interferon-gamma (ifn-γ), il-12, and il-18, type 1 t helper (th2) cytokines: il-4, il-10, il-13, proinflammatory cytokines: il-1α, il-1β, il-6, il-8, il-17, ...201424619468
suramin inhibits ev71 infection.enterovirus-71 (ev71) is one of the major causative reagents for hand-foot-and-mouth disease. in particular, ev71 causes severe central nervous system infections and leads to numerous dead cases. although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. in the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit ev71 p ...201424374150
an inactivated enterovirus 71 vaccine in healthy children.enterovirus 71 (ev71) is a major cause of hand, foot, and mouth disease in children and may be fatal. a vaccine against ev71 is needed.201424571755
efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in china.enterovirus 71 (ev71) is one of the major causative agents of outbreaks of hand, foot, and mouth disease or herpangina worldwide. this phase 3 trial was designed to evaluate the efficacy, safety, and immunogenicity of an ev71 vaccine.201424571754
inhibition of mir-146a prevents enterovirus-induced death by restoring the production of type i interferon.there are no antivirals or vaccines available to treat enterovirus 71 (ev71) infections. although the type i interferon response, elicited upon virus infection, is critical to establishing host antiviral innate immunity, ev71 fails to induce this response efficiently. here we provide new insights into potential anti-ev71 therapy by showing that neutralization of ev71-induced mir-146a prevents death in mice by restarting the production of type i interferon. ev71 infection upregulates mir-146a, wh ...201424561744
toll-like receptor 9-mediated protection of enterovirus 71 infection in mice is due to the release of danger-associated molecular patterns.enterovirus 71 (ev71), a positive-stranded rna virus, is the major cause of hand, foot, and mouth disease (hfmd) with severe neurological symptoms. antiviral type i interferon (alpha/beta interferon [ifn-α/β]) responses initiated from innate receptor signaling are inhibited by ev71-encoded proteases. it is less well understood whether ev71-induced apoptosis provides a signal to activate type i interferon responses as a host defensive mechanism. in this report, we found that ev71 alone cannot act ...201425078697
mrna decay factor auf1 binds the internal ribosomal entry site of enterovirus 71 and inhibits virus replication.au-rich element binding factor 1 (auf1) has a role in the replication cycles of different viruses. here we demonstrate that auf1 binds the internal ribosome entry site (ires) of enterovirus 71 (ev71) and negatively regulates ires-dependent translation. during ev71 infection, auf1 accumulates in the cytoplasm where viral replication occurs, whereas auf1 localizes predominantly in the nucleus in mock-infected cells. auf1 knockdown in infected cells increases ires activity and synthesis of viral pr ...201425077793
the correlation between the presence of viremia and clinical severity in patients with enterovirus 71 infection: a multi-center cohort study.enterovirus 71 (ev71) is a great disease burden across the whole world, particularly in southeast asia. however, in recent decades, the pathogenesis of severe ev71 infection was not well understood. this study was aimed to investigate the correlation between the presence of viremia and the clinical severity of ev71 infection.201425069383
activation of pi3k/akt pathway limits jnk-mediated apoptosis during ev71 infection.apoptosis is frequently induced to inhibit virus replication during infection of enterovirus 71 (ev71). on the contrary, anti-apoptotic pathway, such as pi3k/akt pathway, is simultaneously exploited by ev71 to accomplish the viral life cycle. the relationship by which ev71-induced apoptosis and pi3k/akt signaling pathway remains to be elucidated. in this study, we demonstrated that ev71 infection altered bax conformation and triggered its redistribution from the cytosol to mitochondria in rd cel ...201425116390
the identification and characterization of nucleic acid chaperone activity of human enterovirus 71 nonstructural protein 3ab.human enterovirus 71 (ev71) belongs to the genus enterovirus in the family picornaviridae and has been recognized as one of the most important pathogens that cause emerging infectious disease. despite of the importance of ev71, the nonstructural protein 3ab from this virus is little understood for its function during ev71 replication. here we expressed ev71 3ab protein as recombinant protein in a eukaryotic expression system and uncovered that this protein possesses a nucleic acid helix-destabil ...201425113906
early dexamethasone treatment exacerbates enterovirus 71 infection in mice.enterovirus 71 (ev71) infection can induce encephalitis. overt immune responses is suspected to cause severe symptoms, so anti-inflammatory agents, corticosteroids have been recommended for treatment. however, one clinical study reported that treatment with glucocorticoids, dexamethasone (dex) exacerbates disease severity. here we investigated dex treatment on ev71 infection using the murine model and found that both long-term (14-day) and short-term (4-day) dex treatment starting from 1 or 3 da ...201425104614
the cellular receptor for enterovirus 71. 201425103897
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