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1.
PLoS Pathog ; 16(9): e1008857, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32936838

RESUMO

An outbreak of the hand-foot-mouth disease with severe neurological cases, mainly caused by the genotype C1 enterovirus A71 (EV-A71), occurred in Taiwan between 2018 and early 2019. In the recent decade, the most dominant EV-A71 genotypes in Taiwan were B5 and C4 but changed to C1 in 2018. Antibody-mediated immunity plays a key role in limiting the EV-A71 illness in humans. However, the level of neutralizing activities against genotype C1 virus by human polyclonal and monoclonal antibodies (MAbs) remains largely unclear. In the study, we demonstrated that that 39% (9 in 23) of post-infection sera from the genotype B5- or C4-infected patients in 2014-2017 exhibit reduced titers with the 2018-2019 genotype C1 viruses than with the earlier B5 and C4 viruses tested. This finding with polyclonal sera is confirmed with human MAbs derived from genotype B5 virus-infected individuals. The 2018-2019 genotype C1 virus is resistant to the majority of canyon-targeting human MAbs, which may be associated with the residue change near or at the bottom of the canyon region on the viral capsid. The remaining three antibodies (16-2-11B, 16-3-4D, and 17-1-12A), which target VP1 S241 on the 5-fold vertex, VP3 E81 on the 3-fold plateau and VP2 D84 on the 2-fold plateau of genotype C1 viral capsid, respectively, retained neutralizing activities with variable potencies. These neutralizing antibodies were also found to be protective against a lethal challenge of the 2018-2019 genotype C1 virus in an hSCARB2-transgenic mice model. These results indicate that the EV-A71-specific antibody response may consist of a fraction of poorly neutralizing antibodies against 2018-2019 genotype C1 viruses among a subset of previously infected individuals. Epitope mapping of protective antibodies that recognize the emerging genotype C1 virus has implications for anti-EV-A71 MAbs and the vaccine field.


Assuntos
Antígenos Virais/genética , Enterovirus Humano A/genética , Variação Genética , Genoma Viral , Genótipo , Doença de Mão, Pé e Boca/genética , Animais , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Criança , Pré-Escolar , Enterovirus Humano A/imunologia , Enterovirus Humano A/isolamento & purificação , Feminino , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/imunologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Taiwan
2.
PLoS Negl Trop Dis ; 14(3): e0008124, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32126083

RESUMO

Enterovirus-A71 (EV-A71) cyclically causes hand-foot-mouth disease (HFMD) epidemics in Asian children. An EV-A71 epidemic occurred in Southern Vietnam in 2011, but its scale is not clear. We collected residual sera from non-HFMD Vietnamese inpatients in 2012-2013 to determine seroprevalence of EV-A71 neutralizing antibodies, and measured cross-reactive neutralizing antibody titers against three EV-A71 genogroups. About 23.5% of 1-year-old children in Southern Vietnam has been infected by EV-A71, and the median age of infection was estimated to be 3 years. No significant antigenic variation could be detected among the three EV-A71 genogroups. The high seroprevalence of EV-A71 neutralizing antibody in children living in southern Vietnam indicates the necessity of introducing EV-A71 vaccines in southern Vietnam, particularly for children under 6 months of age. Moreover, it is critical to understand EV-A71 disease burden for formulating national vaccination policy.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Soroepidemiológicos , Vietnã/epidemiologia
3.
Cell Host Microbe ; 27(2): 249-261.e5, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32027857

RESUMO

Hand, foot, and mouth disease is a common childhood illness primarily caused by coxsackievirus A16 (CVA16), for which there are no current vaccines or treatments. We identify three CVA16-specific neutralizing monoclonal antibodies (nAbs) with therapeutic potential: 18A7, 14B10, and NA9D7. We present atomic structures of these nAbs bound to all three viral particle forms-the mature virion, A-particle, and empty particle-and show that each Fab can simultaneously occupy the mature virion. Additionally, 14B10 or NA9D7 provide 100% protection against lethal CVA16 infection in a neonatal mouse model. 18A7 binds to a non-conserved epitope present in all three particles, whereas 14B10 and NA9D7 recognize broad protective epitopes but only bind the mature virion. NA9D7 targets an immunodominant site, which may overlap the receptor-binding site. These findings indicate that CVA16 vaccines should be based on mature virions and that these antibodies could be used to discriminate optimal virion-based immunogens.


Assuntos
Anticorpos Neutralizantes , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/virologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/ultraestrutura , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/ultraestrutura , Proteínas do Capsídeo/imunologia , Linhagem Celular , Microscopia Crioeletrônica , Enterovirus/imunologia , Enterovirus/ultraestrutura , Enterovirus Humano A/ultraestrutura , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Camundongos , Vacinas Virais/imunologia , Vírion/imunologia
4.
J Virol ; 94(6)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31896594

RESUMO

Enterovirus 71 (EV71) is a causative agent of hand-foot-mouth disease, and it sometimes causes severe neurological disease. Development of effective vaccines and animal models to evaluate vaccine candidates are needed. However, the animal models currently used for vaccine efficacy testing, monkeys and neonatal mice, have economic, ethical, and practical drawbacks. In addition, EV71 strains prepared for lethal challenge often develop decreased virulence during propagation in cell culture. To overcome these problems, we used a mouse model expressing human scavenger receptor B2 (hSCARB2) that showed lifelong susceptibility to EV71. We selected virulent EV71 strains belonging to the subgenogroups B4, B5, C1, C2, and C4 and propagated them using a culture method for EV71 without an apparent reduction in virulence. Here, we describe a novel EV71 vaccine efficacy test based on these hSCARB2 transgenic (Tg) mice and these virulent viruses. Adult Tg mice were immunized subcutaneously with formalin-inactivated EV71. The vaccine elicited sufficient levels of neutralizing antibodies in the immunized mice. The mice were subjected to lethal challenge with virulent viruses via intravenous injection. Survival, clinical signs, and body weight changes were observed for 2 weeks. Most immunized mice survived without clinical signs or histopathological lesions. The viral replication in immunized mice was much lower than that in nonimmunized mice. Mice immunized with the EV71 vaccine were only partially protected against lethal challenge with coxsackievirus A16. These results indicate that this new model is useful for in vivo EV71 vaccine efficacy testing.IMPORTANCE The development of new vaccines for EV71 relies on the availability of small animal models suitable for in vivo efficacy testing. Monkeys and neonatal mice have been used, but the use of these animals has several drawbacks, including high costs, limited susceptibility, and poor experimental reproducibility. In addition, the related ethical issues are considerable. The new efficacy test based on hSCARB2 Tg mice and virulent EV71 strains propagated in genetically modified cell lines presented here can overcome these disadvantages and is expected to accelerate the development of new EV71 vaccines.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Glicoproteínas de Membrana Associadas ao Lisossomo/imunologia , Receptores Depuradores/imunologia , Vacinas Virais/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Avaliação de Medicamentos , Enterovirus Humano A/genética , Enterovirus Humano A/patogenicidade , Doença de Mão, Pé e Boca/genética , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/patologia , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Camundongos , Camundongos Transgênicos , Receptores Depuradores/genética , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/farmacologia , Vacinas Virais/genética , Vacinas Virais/imunologia
5.
Emerg Microbes Infect ; 8(1): 1445-1455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31595827

RESUMO

Coxsackievirus A4 (CVA4) infection can cause hand, foot and mouth disease (HFMD), an epidemic illness affecting neonatal and paediatric cohorts, which can develop to severe neurological disease with high mortality. In this study, we established the first ICR mouse model of CVA4 infection for the evaluation of inactivated vaccines and antiviral drug screening. The CVA4 YT226R strain was selected to infect the neonatal mice and three infectious factors were optimized to establish the infection model. The 3-day-old neonatal mice exhibited clinical symptoms such as hind limb paralysis and death. The severe inflammatory reactions were closely related to the abnormal expression of the acute phase response proinflammatory cytokine IL-6 and an imbalance in the IFN-γ/IL-4 ratio. Importantly, the inactivated CVA4 whole-virus vaccine induced humoral immune responses in adult females and the maternal antibodies afforded mice complete protection against lethal dose challenges of homologous or heterologous CVA4 strains. Both IFN-α2a and antiserum inhibited the replication of CVA4 and increased the survival rates of neonatal mice during the early stages of infection. This neonatal murine model of CVA4 infection will be useful for the development of prophylactic and therapeutic vaccines and for screening of antiviral drugs targeting CVA4 to decrease morbidity and mortality.


Assuntos
Anticorpos Antivirais/uso terapêutico , Antivirais/uso terapêutico , Modelos Animais de Doenças , Doença de Mão, Pé e Boca/prevenção & controle , Imunização Passiva , Vacinas Virais/administração & dosagem , Animais , Animais Recém-Nascidos , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Avaliação Pré-Clínica de Medicamentos , Enterovirus/efeitos dos fármacos , Feminino , Doença de Mão, Pé e Boca/imunologia , Imunidade Humoral , Camundongos , Camundongos Endogâmicos ICR , Vacinas de Produtos Inativados/imunologia , Carga Viral , Vacinas Virais/imunologia
6.
J Infect Chemother ; 25(12): 1074-1077, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401030

RESUMO

Enterovirus 71 (EV71), a newly emerging life-threatening pathogen induces hand-foot-mouth disease (HFMD), no effective vaccines or specific anti-viral treatments are currently available. In this study, the activity of hederacolchiside C (HSC) against EV71 was investigated, and the antiviral mechanism was explored. HSC displayed apparent antiviral activity in EV71-infected cells probably through activating the host innate immunity. Comparing with EV71-infected group at 24 hpi, the group pretreated with HSC dramatically increased the expression of MAVS, p-IRF3, IRF3 and IFN-ß, the innate immune effectors related to innate immunity. In addition, HSC displayed stronger antiviral activity in EV71-infected suckling mice in comparison with Ribavirin, a broad-spectrum antiviral drug. The results suggest that HSC could have potential as a pharmaceutical drug for HFMD.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/tratamento farmacológico , Pulsatilla/química , Saponinas/farmacologia , Animais , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Enterovirus Humano A/efeitos dos fármacos , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Camundongos , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Saponinas/uso terapêutico , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia
7.
PLoS One ; 14(5): e0216993, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120941

RESUMO

Hand, foot and mouth disease (HFMD) is an infectious disease that affects mostly children. The children with HFMD also have other immune and metabolic disorders. However, the association of these disorders with the severity of HFMD has not yet been determined. In this study, we used a case-control study design to examine the correlation of immune and metabolic disorders with HFMD development in children. 406 mild and severe patients were recruited and divided into different subgroups based on the number of days from the initial onset time to hospitalization (1, 2, 3, 4, and ≥5 days). Logistic regression model was used to define the predictors of severe HFMD. We found that the patients from rural area (OR = 1.76, 95% CI [1.19~2.63], P = 0.005) or with body temperature of >39°C (OR = 2.14, 95% CI [1.12~4.12], P = 0.022) exhibited higher risk for severe symptoms. In addition, the risk increased with the rise of body temperature by using a Chis-quare trend test (P = 0.01). We also found that a decreased number of eosinophils was an predictor of severe HFMD at 1, 2, 3,and 4 days post infection (dpi). Decreased levels of Na+, Cl-, and creatine kinase were also predictors at 1 and ≥5 dpi. On the other hand, elevated level of globulin was a predictor for severe HFMD at 4 dpi and ≥5 dpi, and the increased number of neutrophils or increased level of alkaline phosphatase posed risk for severe HFMD at 3 and ≥5 dpi. Our results suggested that rural living, hyperpyrexia, changes in the immune system that include the numbers of eosinophils and neutrophils and the levels of IgG and globulin, and metabolic alterations, such as the levels of alkaline phosphatase, Na+, Cl-, and creatine kinase in peripheral blood are predictors of severe HFMD.


Assuntos
Doença de Mão, Pé e Boca/diagnóstico , Doença de Mão, Pé e Boca/imunologia , Adolescente , Adulto , Fosfatase Alcalina/sangue , Biomarcadores/sangue , Temperatura Corporal , Estudos de Casos e Controles , Criança , China , Cloretos/sangue , Eosinófilos/metabolismo , Feminino , Globulinas/análise , Doença de Mão, Pé e Boca/sangue , Hospitalização , Humanos , Sistema Imunitário , Imunoglobulina G/sangue , Inflamação/sangue , Masculino , Análise Multivariada , Análise de Regressão , Fatores de Risco , População Rural , Sódio/sangue , Adulto Jovem
8.
Int Immunopharmacol ; 73: 172-180, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31100712

RESUMO

BACKGROUND: Although γδ T cells have been reported to be closely related to the immunopathogenesis of some viral infectious diseases, the changes or roles of γδ T cells in the development of hand, foot, and mouth disease (HFMD) remain unclear. METHODS: Peripheral γδ T cells and their subsets were determined by surface (γδ TCR, Vδ1 TCR, Vδ2 TCR, CD45RA, and CD27) or intracellular (IFN-γ, TNF-α, CD107a, and Granzyme B) markers in healthy controls (HCs) and HFMD patients with FACS. The plasma levels of IFN-γ, TNF-α, IL-6, and MCP-1 were measured by ELISA. Differences in γδ T cells or their subsets and correlations between γδ T cells and inflammation indicators were statistically analyzed. RESULTS: Compared to HCs, HFMD patients showed increased effector γδ T and TNF-α+γδ T cells and plasma TNF-α levels, especially in severe cases. In addition, significantly increased Vδ1 T and IFN-γ+γδ T cells and other plasma inflammatory cytokines were further found in severe patients. Furthermore, EV71+ severe patients showed significantly increased effector and cytokine-producing γδ T cells, while the EV71- severe patients displayed significantly greater plasma cytokine levels. The percentage of IFN-γ+γδ T or TNF-α+γδ T cells was positively correlated with that of effector γδ T cells. There was a positive correlation between the proportion of Vδ1 T cells and white blood cell (WBC) count or the proportion of IFN-γ+γδ T or TNF-α+γδ T cells and neutrophil (N) count, while there was a negative correlation between Vδ2 T cells and WBC or N count. Moreover, the percentages of Vδ1 T and effector γδ T cells in the acute phase of disease declined significantly to normal levels during the recovery phase. CONCLUSIONS: Increased effector γδ T cells with enhanced cytokine production were remarkably observed in severe HFMD patients, which was also associated with clinical inflammation parameters. These data indicated that γδ T cells might be involved in inflammatory abnormalities in severe HFMD.


Assuntos
Citocinas/imunologia , Doença de Mão, Pé e Boca/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Pré-Escolar , Feminino , Doença de Mão, Pé e Boca/virologia , Herpesvirus Humano 4/genética , Humanos , Lactente , Masculino , RNA Viral
9.
J Interferon Cytokine Res ; 39(7): 421-427, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31090483

RESUMO

The aim of this study was to explore the role of interleukin-37 (IL-37) in imbalance of T helper (Th)17/regulatory T cells (Tregs) in hand, foot, and mouth disease (HFMD). The proportions of CD4+ IL-17A+ Th17 cells and CD4+ CD25+Foxp3+ Tregs in peripheral blood or peripheral blood mononuclear cells (PBMCs) from HFMD patients and healthy controls were measured by fluorescence activated cell sorter. The level of IL-37, IL-10, IL-17A, IL-23, and transforming growth factor ß1 (TGF-ß1) in serum or PBMCs of HFMD patients and control subjects were detected using enzyme-linked immunosorbent assay. Results showed that Th17 cells proportion and IL-17A and IL-23 levels were highly increased, whereas Tregs proportion and IL-10 and TGF-ß1 levels were significantly decreased in HFMD patients. Moreover, IL-37 stimulation elevated Tregs proportion but reduced Th17 cell proportion in subjects with HFMD. On the contrary, we found methylprednisolone pulse therapy/methylprednisolone combinated with intravenous gamma globulin inhibits Th17/Treg imbalance through upregulation of IL-37 in HFMD. In conclusion, IL-37 inhibits the imbalance of Th17/Tregs in HFMD.


Assuntos
Doença de Mão, Pé e Boca/imunologia , Interleucina-1/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Criança , Pré-Escolar , China , Feminino , Doença de Mão, Pé e Boca/diagnóstico , Doença de Mão, Pé e Boca/terapia , Humanos , Masculino
10.
J Virol ; 93(13)2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30996087

RESUMO

Enterovirus A71 (EV-A71) is a major pathogen that causes hand-foot-and-mouth disease (HFMD), which occasionally results in severe neurological complications. In this study, we developed four EV-A71 (rgEV-A71) strains by reverse genetics procedures as possible vaccine candidates. The four rgEV-A71 viruses contained various codon-deoptimized VP1 capsid proteins (VP1-CD) and showed replication rates and antigenicity similar to that of the wild-type virus, while a fifth virus, rg4643C4VP-CD, was unable to form plaques but was still able to be examined by median tissue culture infectious dose (TCID50) titers, which were similar to those of the others, indicating the effect of CD on plaque formation. However, the genome stability showed that there were some mutations which appeared during just one passage of the VP1-CD viruses. Thus, we further constructed VP1-CD rgEV-A71 containing high-fidelity determinants in 3D polymerase (CD-HF), and the number of mutations in CD-HF rgEV-A71 was shown to have decreased. The CD-HF viruses showed less virulence than the parental strain in a mouse infection model. After 14 days postimmunization, antibody titers had increased in mice infected with CD-HF viruses. The mouse antisera showed similar neutralizing antibody titers against various CD-HF viruses and different genotypes of EV-A71. The study demonstrates the proof of concept that VP1 codon deoptimization combined with high-fidelity 3D polymerase decreased EV-A71 mutations and virulence in mice but retained their antigenicity, indicating it is a good candidate for next-generation EV-A71 vaccine development.IMPORTANCE EV-A71 can cause severe neurological diseases with fatality in infants and young children, but there are still no effective drugs to date. Here, we developed a novel vaccine strategy with the combination of CD and HF substitutions to generate the genetically stable reverse genetics virus. We found that CD combined with HF polymerase decreased the virulence but maintained the antigenicity of the virus. This work demonstrated the simultaneous introduction of CD genome sequences and HF substitutions as a potential new strategy to develop attenuated vaccine seed virus. Our work provides insight into the development of a low-virulence candidate vaccine virus through a series of genetic editing of virus sequences while maintaining its antigenicity and genome stability, which will provide an additional strategy for next-generation vaccine development of EV-A71.


Assuntos
Proteínas do Capsídeo/imunologia , Códon , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/prevenção & controle , Enterovirus/imunologia , Imunogenicidade da Vacina/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes , Antígenos Virais/genética , Antígenos Virais/imunologia , Sequência de Bases , Proteínas do Capsídeo/genética , Enterovirus/genética , Enterovirus/crescimento & desenvolvimento , Enterovirus Humano A/genética , Enterovirus Humano A/imunologia , Infecções por Enterovirus/virologia , Instabilidade Genômica , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Virulência , Replicação Viral
11.
Sci Rep ; 9(1): 4805, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30886246

RESUMO

Besides causing mild hand, foot and mouth infections, Enterovirus A71 (EV-A71) is associated with neurological complications and fatality. With concerns about rising EV-A71 virulence, there is an urgency for more effective vaccines. The live attenuated vaccine (LAV) is a more valuable vaccine as it can elicit both humoral and cellular immune responses. A miRNA-based vaccine strain (pIY) carrying let-7a and miR-124a target genes in the EV-A71 genome which has a partial deletion in the 5'NTR (∆11 bp) and G64R mutation (3Dp°l) was designed. The viral RNA copy number and viral titers of the pIY strain were significantly lower in SHSY-5Y cells that expressed both let-7a and miR-124a. Inhibition of the cognate miRNAs expressed in RD and SHSY-5Y cells demonstrated de-repression of viral mRNA translation. A previously constructed multiply mutated strain, MMS and the pIY vaccine strain were assessed in their ability to protect 4-week old mice from hind limb paralysis. The MMS showed higher amounts of IFN-γ ex vivo than the pIY vaccine strain. There was absence of EV-A71 antigen in the skeletal muscles and spinal cord micrographs of mice vaccinated with the MMS and pIY strains. The MMS and pIY strains are promising LAV candidates developed against severe EV-A71 infections.


Assuntos
Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Vacinas Virais/administração & dosagem , Virulência/genética , Animais , Antígenos Virais/análise , Antígenos Virais/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Enterovirus Humano A/genética , Enterovirus Humano A/isolamento & purificação , Genoma Viral/genética , Doença de Mão, Pé e Boca/diagnóstico , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/virologia , Humanos , Imunidade Celular , Imunidade Humoral , Imunogenicidade da Vacina , Camundongos , MicroRNAs/genética , Mutação , RNA Viral/isolamento & purificação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Carga Viral , Vacinas Virais/genética , Vacinas Virais/imunologia , Replicação Viral/imunologia
12.
Int J Mol Sci ; 20(6)2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871133

RESUMO

Hand, foot, and mouth disease (HFMD) commonly produces herpangina, but fatal neurological complications have been observed in children. Enterovirus 71 (EV-A71) and Coxsackievirus 16 (CV-A16) are the predominant viruses causing HFMD worldwide. With rising concern about HFMD outbreaks, there is a need for an effective vaccine against EV-A71 and CV-A16. Although an inactivated vaccine has been developed against EV-A71 in China, the inability of the inactivated vaccine to confer protection against CV-A16 infection and other HFMD etiological agents, such as CV-A6 and CV-A10, necessitates the exploration of other vaccine platforms. Thus, the antigenic peptide-based vaccines are promising platforms to develop safe and efficacious multivalent vaccines, while the monoclonal antibodies are viable therapeutic and prophylactic agents against HFMD etiological agents. This article reviews the available information related to the antigenic peptides of the etiological agents of HFMD and their neutralizing antibodies that can provide a basis for the design of future therapies against HFMD etiological agents.


Assuntos
Anticorpos Neutralizantes/imunologia , Doença de Mão, Pé e Boca/imunologia , Peptídeos/imunologia , Vacinas de Subunidades/imunologia , Vacinas Virais/imunologia , Animais , Enterovirus/imunologia , Enterovirus Humano A/imunologia , Humanos
13.
Expert Rev Anti Infect Ther ; 17(4): 233-242, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30793637

RESUMO

INTRODUCTION: Hand, foot, and mouth disease (HFMD) is a common viral childhood illness, that has been a severe public health concern worldwide, particularly in the Asia-Pacific region. According to epidemiological data of HFMD during the past decade, the most prevalent causal viruses were enterovirus (EV)-A71, coxsackievirus (CV)-A16, CV-A6, and CV-A10. The public health burden of CV-A10-related diseases has been underestimated as their incidence was lower than that of EV-A71 and CV-A16 in most HFMD outbreaks. However, cases of CV-A10 infection are more severe, and its genome is more variable, which has alerted the research community worldwide. Areas covered: In this paper, studies on the epidemiology, laboratory diagnosis, clinical manifestations, molecular epidemiology, seroepidemiology, animal models of CV-A10, and vaccines and antiviral strategies against this genotype are reviewed. In addition, the genetic evolution of circulating strains was analyzed. Expert opinion: Multivalent vaccines against EV-A71, CV-A16, CV-A6, and CV-A10 should be a next-step HFMD vaccine strategy.


Assuntos
Enterovirus Humano A/isolamento & purificação , Doença de Mão, Pé e Boca/epidemiologia , Animais , Antivirais/administração & dosagem , Criança , Surtos de Doenças , Enterovirus Humano A/genética , Enterovirus Humano A/imunologia , Genótipo , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Estudos Soroepidemiológicos , Vacinas Virais/administração & dosagem
14.
Hum Vaccin Immunother ; 15(10): 2343-2350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30735461

RESUMO

Coxsackievirus A16 (CA16) has caused worldwide epidemics of hand, foot and mouth disease (HFMD), particularly in infants and pre-school children. Currently, there are no vaccines or antiviral drugs available for CA16-associated disease. In this study, a CA16-specific monoclonal antibody (MAb) NA11F12 was derived with an epidemic CA16 strain (GenBank no. JX127258). NA11F12 was found to have high cross-neutralization activity against different CA16 subgenotypes but not EV71 using RD cells. The neutralizing titers of NA11F12 ranged from 1:1024 to 1:12288 against A, B1, B2 and C subgenotypes of CA16 and was less than 8 against EV71 strain. In the neonatal mouse model, a single treatment of NA11F12 showed effective protection with a dose- and time-dependent relationship against lethal challenge by CA16 strain (GenBank no. JX481738). At day 1 post-infection, administering more than 0.1 µg/g of NA11F12 could protect 100% newborn mice from mobility and mortality challenged by CA16. With dose of 10 µg/g of NA11F12, a single administration fully protected mice against CA16-associated disease within 4 days post-infection. And there were 80% and 60% mice protected by administering NA11F12 at day 5 post-infection and day 6 post-infection when the control mice had shown clinical symptoms for 1- and 2-day, respectively. Immunohistochemical and histological analysis confirmed that NA11F12 significantly prohibited CA16 VP1 expression in various tissues and prevented CA16-induced necrosis. In conclusion, a CA16-specific MAb NA11F12 with high cross-neutralization activity was identified, which could effectively protect lethal CA16 challenge in mice. It could be a potential therapeutic MAb against CA16 in the future.


Assuntos
Anticorpos Antivirais/uso terapêutico , Anticorpos Amplamente Neutralizantes/uso terapêutico , Enterovirus Humano A/imunologia , Doença de Mão, Pé e Boca/prevenção & controle , Animais , Animais Recém-Nascidos , Doença de Mão, Pé e Boca/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Vacinas Virais
15.
Sci Total Environ ; 663: 60-67, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30708217

RESUMO

BACKGROUND: Perfluoroalkyl substances (PFASs) are synthetic chemicals widely used in industry and for commercial products. Their immunomodulatory effects are a growing health concern in children. Hand, Foot and Mouth Disease (HFMD) is a common childhood viral infection, and increased incidence of which has parallel the rise in PFAS exposure in the Asia-Pacific region. OBJECTIVE: We conducted the first study to assess whether prenatal exposure to PFAS was associated with a reduction in HFMD virus antibodies in infants. METHODS: We enrolled 201 mother-infant pairs from the Guangzhou Birth Cohort Study from July to October 2013. High performance liquid chromatography-mass spectrometry was employed to determine concentrations of specific PFAS isomers in cord blood. Neutralizing antibodies titers were measured against two HFMD viruses, enterovirus 71 (EV71) and coxsackievirus A 16 (CA16), in cord blood serum and blood serum at three months of age. RESULTS: Higher umbilical cord blood PFAS concentrations were associated with lower EV71 and CA16 antibody concentrations. A doubling in the composite sum of cord blood PFASs in three month old infants was associated with significant increase in the risk of HFMD antibody concentration below clinical protection level (≥1:8 titers) for CA16 (odds ratio, OR: 2.74 [95% confidence interval (CI): 1.33, 5.61] and for EV71 (OR = 4.55, 95% CI: 1.45, 4.28). This association was higher in boys at three months of age for CA16. CONCLUSIONS: Our findings suggest that cord blood PFAS exposure is associated with lower HFMD antibody in infancy. Given the widespread nature of PFAS exposures and the high global incidence of HFMD globally, these findings have substantial public health implications and therefore, these associations need to be replicated in a larger study to more definitively address the risk.


Assuntos
Anticorpos Antivirais/imunologia , Fluorcarbonetos/efeitos adversos , Vírus da Febre Aftosa/imunologia , Doença de Mão, Pé e Boca/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , China , Estudos de Coortes , Feminino , Sangue Fetal/química , Humanos , Lactente , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/virologia , Fatores Sexuais , Adulto Jovem
16.
Vaccine ; 37(8): 1109-1117, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30683510

RESUMO

Although coxsackievirus A6 (CV-A6) is generally recognized as a causative agent of herpangina in children, CV-A6 infections globally emerged as a new and major cause of epidemic hand-foot-and-mouth-diseases (HFMDs) around 2008. To clarify the longitudinal epidemiology of CV-A6, we carried out sequence and phylogenetic analyses for the VP1 and partially for the VP4-3D regions as well as antigenic analysis using 115 CV-A6 isolates and 105 human sera in Yamagata, Japan between 2001 and 2017. Phylogenetic analysis revealed that CV-A6 isolates were clearly divided into two clusters; strains in circulation between 2001 and 2008 and those between 2010 and 2017. Neutralizing antibody titers of two rabbit antisera, which were immunized with Yamagata isolates in 2001 and 2015, respectively, against 28 Yamagata representative strains as well as the prototype Gdula strain were 1:2560-1:5120 and 1:160-1:640, respectively. The neutralizing antibody titers among residents in Yamagata against the above two strains were similar. Our analyses revealed that there were cross-antigenicities among all analyzed CV-A6 strains, although the newly emerged strains were introduced into Yamagata around 2010 and replaced the previous ones. With regard to control measures, these findings suggest that we can prevent CV-A6 infections through the development of a vaccine that effectively induces neutralizing antibodies against CV-A6, irrespective of genetic cluster.


Assuntos
Enterovirus/genética , Enterovirus/imunologia , Doença de Mão, Pé e Boca/virologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Criança , Pré-Escolar , Enterovirus/isolamento & purificação , Feminino , Genótipo , Doença de Mão, Pé e Boca/imunologia , Humanos , Japão , Masculino , Epidemiologia Molecular/métodos , Filogenia , Coelhos , Análise de Sequência de DNA
17.
Clin Exp Immunol ; 196(3): 353-363, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30697697

RESUMO

A minority of hand, foot and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) results in severe neural complications. However, whether monocyte-mediated immunity is involved in the disease progression of HFMD remains unknown. One hundred and twenty mild and 103 severe HFMD patients were recruited and enzyme-linked immunosorbent assay (ELISA), flow cytometry and Transwell culture were performed in the study. Peripheral monocyte counts were lower in both absolute counts and frequencies in severe cases compared to mild cases. After screening 10 monocyte-related cytokines by ELISA, only monocyte chemoattractant protein-1 (MCP-1) was found at higher levels in sera of mild cases compared to those with severe symptoms. Monocytes purified from mild cases produced more MCP-1 than the cells from severe patients when stimulated in vitro. We observed that immune exhaustion markers programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) were highly regulated on the surface of monocytes from severe cases compared to mild cases. PD-L1 blockade induced a higher production of MCP-1 in the supernatant of a Transwell system. The production of MCP-1 also increased following PD-L1 blockade of purified monocytes activated by granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with R848 or EV-A71 virus. Our results indicate that absolute count, frequency and levels of MCP-1 secretion of peripheral monocytes, together with their immune status, probably contribute to differential disease prognosis in EV-A71-associated HFMD.


Assuntos
Biomarcadores/sangue , Quimiocina CCL2/sangue , Enterovirus Humano A/fisiologia , Doença de Mão, Pé e Boca/imunologia , Monócitos/imunologia , Anticorpos Bloqueadores/metabolismo , Antígeno B7-H1/metabolismo , Células Cultivadas , Senescência Celular , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Doença de Mão, Pé e Boca/diagnóstico , Humanos , Imunidade Celular , Lactente , Contagem de Leucócitos , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais
18.
Appl Microbiol Biotechnol ; 103(4): 1931-1938, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30617817

RESUMO

Coxsackievirus A10 (CVA10) recently has become one of the major pathogens of hand, foot, and mouth disease (HFMD) in children worldwide, but no cure or vaccine against CVA10 is available yet. Serological evaluation of herd immunity to CVA10 will promote the development of vaccine. The traditional neutralization assay based on inhibition of cytopathic effect (Nt-CPE) is a common method for measuring neutralizing antibody titer against CVA10, which is time-consuming and labor-intensive. In this study, an efficient neutralization test based on a monoclonal antibody (mAb) 3D1 against CVA10, called Elispot-based neutralization test (Nt-Elispot), was developed. In the Nt-Elispot, the mAb 3D1 labeled with horseradish peroxidase (HRP) was used to detect the CVA10-infected RD cells at a 1:4000 dilution and the optimal infectious dose of CVA10 was set at 105 TCID50/well when combined with a fixed incubation time of 14 h. Compared with the Nt-CPE, the Nt-Elispot method effectively shortened the detection period and presented a good correlativity with it. Using the Nt-Elispot, a total of 123 sera from healthy children were tested for neutralizing antibody against CVA10, demonstrating that the overall seroprevalence was 49.3% (54/123) and the geometric mean titer (GMT) had been calculated as 574.2. Furthermore, 2 anti-CVA10 neutralizing mAbs were obtained by screening via the Nt-Elispot. Overall, the established Nt-Elispot could be used as an efficient and high-throughput method for evaluating immunity to CVA10 and screening the neutralizing antibodies.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Enterovirus/imunologia , Doença de Mão, Pé e Boca/imunologia , Testes de Neutralização/métodos , Pré-Escolar , Ensaios de Triagem em Larga Escala/métodos , Humanos , Lactente , Estudos Soroepidemiológicos
19.
PLoS One ; 13(10): e0202552, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30278051

RESUMO

Enterovirus 71 (EV71) is a major etiological agent of various public health issues, particularly in the Asia-Pacific region. EV71 causes hand-foot-and-mouth disease (HFMD) and is associated with serious neurological disorders in young children. A formalin-inactivated EV71 candidate vaccine (KCDC-HFMDV1-EV71) based on the C4 subgenotype was previously developed and confirmed to be a potential candidate vaccine for prevention of EV71 infection in mice. In this study, an inactivated EV71 vaccine was used for analysis of long-term immunogenicity and efficacy in cynomolgus monkeys, a common nonhuman primate model. The vaccine was immunized three times at 0, 4, and 8 weeks with either 20-µg doses of EV71 candidate vaccine formulated with aluminum hydroxide gel adjuvant or phosphate-buffered saline as a control. The group immunized with the inactivated EV71 showed significantly increased EV71-specific antibody and serum neutralizing antibody titers at 3 weeks after vaccination and maintained these elevated titers until the end of the experiment (54 weeks after vaccination). The sera from vaccinated cynomolgus monkeys showed a crossreactive neutralizing antibody response to the heterologous subtype of EV71 (B1-4, C1, and C2). These findings suggest that the inactivated EV71 candidate vaccine may be a potential vaccine candidate and valuable tool for the control of HFMD.


Assuntos
Enterovirus Humano A/imunologia , Infecções por Enterovirus/prevenção & controle , Doença de Mão, Pé e Boca/prevenção & controle , Vacinas de Produtos Inativados/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Doença de Mão, Pé e Boca/imunologia , Humanos , Macaca fascicularis/imunologia , Macaca fascicularis/virologia , Camundongos , Vacinação , Vacinas de Produtos Inativados/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia
20.
Microb Pathog ; 125: 7-11, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30193952

RESUMO

Coxsackievirus A6 (CV-A6) has recently emerged as an enterovirus causing Hand Foot and Mouth Disease with severe complications. The pathogenic mechanisms of CV-A6- associated Hand foot and Mouth disease are largely unknown. In this study, it was investigated whether serum and IgG from patients with CV-A6 infection can enhance the infection of PBMC with the virus. Serum samples were obtained from five children with CV-A6 infection confirmed by RT-PCR and seven controls. IgG was isolated from serum by using affinity chromatography columns. CV-A6 was incubated with serum or IgG from controls and patients then the mixtures were added to PBMC cultures. The levels of IFNα in supernatants were measured by ELISA, and the levels of intracellular viral RNA were measured by RT-qPCR. It has been observed that there is an anti-CV-A6 enhancing activity in serum and serum-derived immunoglobulin G of children with CV-A6 infection but not in those of uninfected controls. Whether this activity has implications in the pathogenesis of CV-A6 associated diseases should be investigated.


Assuntos
Anticorpos Antivirais/metabolismo , Anticorpos Facilitadores , Enterovirus/crescimento & desenvolvimento , Enterovirus/imunologia , Imunoglobulina G/metabolismo , Leucócitos Mononucleares/virologia , Anticorpos Antivirais/sangue , Células Cultivadas , Criança , Pré-Escolar , Citoplasma/virologia , Feminino , Doença de Mão, Pé e Boca/imunologia , Doença de Mão, Pé e Boca/virologia , Humanos , Masculino , RNA Viral/análise , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Viral
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