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1.
Stem Cell Reports ; 16(3): 493-504, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33626333

RESUMO

Enteroviruses, such as EV-A71 and CVA16, mainly infect the human gastrointestinal tract. Human coronaviruses, including SARS-CoV and SARS-CoV-2, have been variably associated with gastrointestinal symptoms. We aimed to optimize the human intestinal organoids and hypothesize that these optimized intestinal organoids can recapitulate enteric infections of enterovirus and coronavirus. We demonstrate that the optimized human intestinal organoids enable better simulation of the native human intestinal epithelium, and that they are significantly more susceptible to EV-A71 than CVA16. Higher replication of EV-A71 than CVA16 in the intestinal organoids triggers a more vigorous cellular response. However, SARS-CoV and SARS-CoV-2 exhibit distinct dynamics of virus-host interaction; more robust propagation of SARS-CoV triggers minimal cellular response, whereas, SARS-CoV-2 exhibits lower replication capacity but elicits a moderate cellular response. Taken together, the disparate profile of the virus-host interaction of enteroviruses and coronaviruses in human intestinal organoids may unravel the cellular basis of the distinct pathogenicity of these viral pathogens.


Assuntos
/virologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/virologia , Intestinos/virologia , Organoides/virologia , /patogenicidade , Animais , Linhagem Celular , Chlorocebus aethiops , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Mucosa Intestinal/virologia , Células Vero , Replicação Viral/fisiologia
2.
Arch Virol ; 166(4): 1203-1211, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33606112

RESUMO

Lactoferrin is part of the innate immune system, with antiviral activity against numerous DNA and RNA viruses. Rhinoviruses, the leading cause of the common cold, are associated with exacerbation of respiratory illnesses such as asthma. Here, we explored the effect of bovine lactoferrin (BLf) on RV-B14 infectivity. Using different assays, we show that the effect of BLf is strongest during adhesion of the virus to the cell and entry. Tracking the internalisation of BLf and virus revealed a degree of colocalisation, although their interaction was only confirmed in vitro using empty viral particles, indicating a possible additional influence of BLf on other infection steps.


Assuntos
Antivirais/farmacologia , Enterovirus/efeitos dos fármacos , Lactoferrina/farmacologia , Internalização do Vírus/efeitos dos fármacos , Antivirais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Enterovirus/fisiologia , Infecções por Enterovirus/virologia , Células HeLa , Humanos , Lactoferrina/metabolismo , Ligação Viral/efeitos dos fármacos
3.
Artigo em Inglês | MEDLINE | ID: mdl-33573536

RESUMO

Abstract: Significant reductions in the incidence of enteroviruses and noroviruses, both transmitted primarily by the faecal-oral route, were noted in 2020 compared to the previous decade, in Victoria, Australia. The enterovirus specimen positivity rate was reduced by 84.2% in 2020, while the norovirus outbreak positivity rate declined by 49.0%. The most likely explanation for these reductions is the concurrence of social restrictions, physical distancing, personal hygiene awareness and international and domestic border closures in response to the COVID-19 pandemic.


Assuntos
/epidemiologia , Infecções por Caliciviridae/virologia , Enterovirus , Gastroenterite/epidemiologia , Gastroenterite/virologia , Norovirus , Infecções por Caliciviridae/epidemiologia , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Humanos , Incidência , Vitória/epidemiologia
4.
Medicine (Baltimore) ; 100(7): e24855, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607859

RESUMO

BACKGROUND: To analyze the prevalence of latent infection of pathogens of hand, foot, and mouth disease (HFMD) in Chinese healthy population and its influencing factors, so as to provide reference for the prevention and control of HFMD. METHODS: A systematic literature searching about the incidence of latent infection of HFMD was conducted in Chinese and English databases. The inclusion and exclusion criteria of the retrieved literature were established. The qualified literatures were screened and the data were extracted. The pooled rate and its 95% confidence interval was used to assess the latent infection rate of HFMD pathogens in healthy Chinese population, and subgroup analysis was conducted based on gender and age. All statistical analyses were performed using the STATA version 12.0 software. RESULTS: A total of 31 literatures were included in this meta-analysis. The recessive infection rate of HFMD pathogens reported in the literature of Chinese healthy people ranged from 4.59% to 44.12%. The results of meta-analysis showed that the latent infection rate of human enteroviruses (HEVs) in healthy Chinese population was 17.5% (14.9-20.1%), among which, the latent infection rates of EV-A71, CV-A16, and other HEVs were 3.3% (2.2-4.4%), 1.7% (1.0-2.5%), and 15.1% (11.1-17.1%), respectively. The latent infection rates of HEVs in healthy men and women in China were 16.7% (12.9-20.4%) and 14.4% (10.8-18.0%), respectively. The latent infection rates of HEVs in the healthy population aged 0 to 5 years and over 5 years were 24.4% (20.4-28.5%) and 9.4% (6.5-12.2%), respectively. Meta regression showed that the factors affecting the latent infection rate of HEVs in Chinese healthy population included sampling period, sampling area, and study population. CONCLUSION: The latent infection rate of HEVs is high in healthy people in China, but it is mainly caused by other enteroviruses. The latent infection rate of HEVs in male was higher than that of female and was greater in people aged 0 to 5 than that of aged over 5 years. Limited by the quantity and quality of the included studies, more high-quality studies are needed for further verification in the future.


Assuntos
Infecções Assintomáticas/epidemiologia , Doença de Mão, Pé e Boca/epidemiologia , Voluntários Saudáveis/estatística & dados numéricos , /epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , China/epidemiologia , Estudos Transversais , Gerenciamento de Dados , Enterovirus/genética , Enterovirus/isolamento & purificação , Enterovirus/patogenicidade , Enterovirus Humano A/genética , Enterovirus Humano A/isolamento & purificação , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Feminino , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Prevalência , Adulto Jovem
5.
Viruses ; 13(2)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499226

RESUMO

Cadherin Related Family Member 3 (CDHR3) is the identified and required cellular receptor for all virus isolates in the rhinovirus-C species (RV-C). Cryo-EM determinations recently resolved the atomic structure of RV-C15a, and subsequently, a complex of this virus bound to CDHR3 extracellular domain 1 (EC1), the N-terminal portion of this receptor responsible for virus interactions. The EC1 binds to a hypervariable sequence footprint on the virus surface, near the 3-fold axis of icosahedral symmetry. The key contacts involve discontinuous residues from 3 viral proteins, VP1, VP2 and VP3. That single cryo-EM EC1 structure, however, could not resolve whether the virus-receptor interface was structurally adaptable to accommodate multiple virus sequences. We now report the solution NMR determination of CDHR3 EC1, showing that this protein, in fact, is mostly inflexible, particularly in the virus-binding face. The new, higher resolution dataset identifies 3 cis-Pro residues in important loop regions, where they can influence both rigidity and overall protein conformation. The data also provide clarification about the residues involved in essential calcium ion binding, and a potential CDHR3 surface groove feature that may be involved in native protein interactions with cellular partners.


Assuntos
Caderinas/química , Enterovirus/química , Proteínas de Membrana/química , Enterovirus/classificação , Infecções por Enterovirus/virologia , Humanos , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Estrutura Terciária de Proteína , Proteínas Virais/química , Ligação Viral
6.
Viruses ; 13(1)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430521

RESUMO

We describe the complete capsid of a genotype C1-like Enterovirus A71 variant recovered from wastewater in a neighborhood in the greater Tempe, Arizona area (Southwest United States) in May 2020 using a pan-enterovirus amplicon-based high-throughput sequencing strategy. The variant seems to have been circulating for over two years, but its sequence has not been documented in that period. As the SARS-CoV-2 pandemic has resulted in changes in health-seeking behavior and overwhelmed pathogen diagnostics, our findings highlight the importance of wastewater-based epidemiology (WBE ) as an early warning system for virus surveillance.


Assuntos
Proteínas do Capsídeo/genética , Enterovirus Humano A/genética , Enterovirus Humano A/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Águas Residuárias/virologia , Vigilância Epidemiológica Baseada em Águas Residuárias , Arizona/epidemiologia , Capsídeo/química , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Humanos , Epidemiologia Molecular , Pandemias , Filogenia
7.
Artigo em Inglês | MEDLINE | ID: mdl-33401757

RESUMO

(1) Background: Assignment of pathogens to the correct genus, species, and type is vital for controlling infectious epidemics. However, the role of different enteroviruses during hand, foot, and mouth disease (HFMD) epidemics and the major contributing factors remain unknown. (2) Methods: HFMD cases from 2016 to 2018 in Guangzhou, China were collected. The relationship between HFMD cases and genotype frequency, as well as the association between genotype frequency and climate factors, were studied using general linear models. We transformed the genotype frequency to the isometric log-ratio (ILR) components included in the model. Additionally, vaccination rates were adjusted in the climate-driven models. (3) Results: We observed seasonal trends in HFMD cases, genotype frequency, and climate factors. The model regressing case numbers on genotype frequency revealed negative associations with both the ILRs of CAV16 (RR = 0.725, p < 0.001) and EV71 (RR = 0.421, p < 0.001). The model regressing genotype frequency on driven factors showed that the trends for EV71 proportions were inversely related to vaccination rate (%, ß = -0.152, p = 0.098) and temperature (°C, ß = -0.065, p = 0.004). Additionally, the trends for CVA16 proportions were inversely related to vaccination rate (%, ß = -0.461, p = 0.004) and temperature (°C, ß = -0.068, p = 0.031). The overall trends for genotype frequency showed that EV71 decreased significantly, while the trends for CVA16 increased annually. (4) Conclusions: Our findings suggest a potential pathway for climate factors, genotype frequency, and HFMD cases. Our study is practical and useful for targeted prevention and control, and provides environmental-based evidence.


Assuntos
Clima , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Enterovirus/genética , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/virologia , Vacinação/estatística & dados numéricos , China/epidemiologia , Feminino , Genótipo , Humanos , Modelos Lineares , Masculino , Filogenia , Vigilância da População , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Viruses ; 13(1)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33451106

RESUMO

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a multifactorial disease in which dietary, genetic, immunological, and microbial factors are at play. The role of enteric viruses in IBD remains only partially explored. To date, epidemiological studies have not fully described the role of enteric viruses in inflammatory flare-ups, especially that of human noroviruses and rotaviruses, which are the main causative agents of viral gastroenteritis. Genome-wide association studies have demonstrated the association between IBD, polymorphisms of the FUT2 and FUT3 genes (which drive the synthesis of histo-blood group antigens), and ligands for norovirus and rotavirus in the intestine. The role of autophagy in defensin-deficient Paneth cells and the perturbations of cytokine secretion in T-helper 1 and T-helper 17 inflammatory pathways following enteric virus infections have been demonstrated as well. Enteric virus interactions with commensal bacteria could play a significant role in the modulation of enteric virus infections in IBD. Based on the currently incomplete knowledge of the complex phenomena underlying IBD pathogenesis, future studies using multi-sampling and data integration combined with new techniques such as human intestinal enteroids could help to decipher the role of enteric viruses in IBD.


Assuntos
Suscetibilidade a Doenças , Infecções por Enterovirus/complicações , Infecções por Enterovirus/virologia , Enterovirus/fisiologia , Interações Hospedeiro-Patógeno , Doenças Inflamatórias Intestinais/etiologia , Animais , Autofagia , Biomarcadores , Antígenos de Grupos Sanguíneos/genética , Antígenos de Grupos Sanguíneos/imunologia , Gerenciamento Clínico , Infecções por Enterovirus/epidemiologia , Microbioma Gastrointestinal , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Interações Microbianas , Transdução de Sinais
9.
Viruses ; 13(1)2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33477302

RESUMO

The knowledge about circulation of Human Enteroviruses (EVs) obtained through medical diagnosis in Argentina is scarce. Wastewater samples monthly collected in Córdoba, Argentina during 2011-2012, and then in 2017-2018 were retrospectively studied to assess the diversity of EVs in the community. Partial VP1 gene was amplified by PCR from wastewater concentrates, and amplicons were subject of next-generation sequencing and genetic analyses. There were 41 EVs detected, from which ~50% had not been previously reported in Argentina. Most of the characterized EVs (60%) were detected at both sampling periods, with similar values of intratype nucleotide diversity. Exceptions were enterovirus A71, coxsackievirus B4, echovirus 14, and echovirus 30, which diversified in 2017-2018. There was a predominance of types from EV-C in 2017-2018, evidencing a common circulation of these types throughout the year in the community. Interestingly, high genetic similarity was evidenced among environmental strains of echovirus 30 circulating in 2011-2012 and co-temporal isolates obtained from patients suffering aseptic meningitis in different locations of Argentina. This study provides an updated insight about EVs circulating in an important region of South America, and suggests a valuable role of wastewater-based epidemiology in predicting outbreaks before the onset of cases in the community.


Assuntos
Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Enterovirus/genética , Microbiologia Ambiental , Monitoramento Ambiental , Variação Genética , Argentina/epidemiologia , Biologia Computacional/métodos , Enterovirus/classificação , Enterovirus/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Filogenia , Vigilância em Saúde Pública , Carga Viral , Águas Residuárias/microbiologia , Águas Residuárias/virologia
10.
Viruses ; 13(1)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450832

RESUMO

Limited recent molecular epidemiology data are available for pediatric Central Nervous System (CNS) infections in Europe. The aim of this study was to investigate the molecular epidemiology of enterovirus (EV) involved in CNS infections in children. Cerebrospinal fluid (CSF) from children (0-16 years) with suspected meningitis-encephalitis (ME) who were hospitalized in the largest pediatric hospital of Greece from October 2017 to September 2020 was initially tested for 14 common pathogens using the multiplex PCR FilmArray® ME Panel (FA-ME). CSF samples positive for EV, as well as pharyngeal swabs and stools of the same children, were further genotyped employing Sanger sequencing. Of the 330 children tested with FA-ME, 75 (22.7%) were positive for EV and 50 different CSF samples were available for genotyping. The median age of children with EV CNS infection was 2 months (IQR: 1-60) and 44/75 (58.7%) of them were male. There was a seasonal distribution of EV CNS infections, with most cases detected between June and September (38/75, 50.7%). EV genotyping was successfully processed in 84/104 samples: CSF (n = 45/50), pharyngeal swabs (n = 15/29) and stools (n = 24/25). Predominant EV genotypes were CV-B5 (16/45, 35.6%), E30 (10/45, 22.2%), E16 (6/45, 13.3%) and E11 (5/45, 11.1%). However, significant phylogenetic differences from previous described isolates were detected. No unusual neurologic manifestations were observed, and all children recovered without obvious acute sequelae. Specific EV circulating genotypes are causing a significant number of pediatric CNS infections. Phylogenetic analysis of these predominant genotypes found genetic differences from already described EV isolates.


Assuntos
Infecções do Sistema Nervoso Central/epidemiologia , Infecções do Sistema Nervoso Central/virologia , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Enterovirus/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Enterovirus/classificação , Feminino , Genoma Viral , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Epidemiologia Molecular , Estrutura Molecular , Filogenia , Vigilância em Saúde Pública
11.
J Ethnopharmacol ; 266: 113401, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32980486

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of traditional Chinese medicine, the main pathogenesis of severe hand, foot and mouth disease (HFMD) is that the heat and wet poisons are deeply trapped in the viscera, which causes the deficiency of Qi and Yin in the patient's body. Ginsenoside Rb1 (Rb1) is the most abundant triterpenoid saponin in Panax quinquefolius L., which has the function of Qi-invigorating and Yin-nourishing. Enterovirus 71 (EV71) is one of the causative pathogens of HFMD, especially the form associated with some lethal complications. Therefore, the therapeutic effect of Rb1 on this disease caused by EV71 infection is worth exploring. AIM OF THE STUDY: We explored the effective antiviral activities of Rb1 against EV71 in vitro and in vivo and investigated its preliminary antiviral mechanisms. MATERIAL AND METHODS: EV71-infected two-day-old suckling mice model was employed to detect the antiviral effects of Rb1 in vivo. To detect the antiviral effects of Rb1 in vitro, cytopathic effect (CPE) reduction assay was performed in EV71-infected Rhabdomyosarcoma (RD) cells. Interferon (IFN)-ß interference experiment was employed to detect the antiviral mechanism of Rb1. RESULTS: In this paper, we first found that Rb1 exhibited strong antiviral activities in EV71-infected suckling mice when compared to those of ribavirin. Administration of Rb1 reduced the CPE of EV71-infected RD cells in a dose-dependent manner. Moreover, EV71-induced viral protein-1 (VP-1) expression was significantly reduced by Rb1 administration in vitro and in vivo. Furthermore, Rb1 treatment could induce high cellular and humoral immune responses in vivo. Meanwhile, Rb1 contributed to the enhanced Type I IFN responses and IFN-ß knockdown reversed the antiviral activity of Rb1 in vitro. CONCLUSION: In summary, our findings suggest that Rb1 is an immune-stimulatory agent and provide an insight into therapeutic potentials of Rb1 for the treatment of EV71 infection.


Assuntos
Antivirais/farmacologia , Enterovirus Humano A/efeitos dos fármacos , Infecções por Enterovirus/tratamento farmacológico , Ginsenosídeos/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Animais , Antivirais/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infecções por Enterovirus/virologia , Ginsenosídeos/administração & dosagem , Humanos , Camundongos , Camundongos Endogâmicos ICR , Panax/química , Rabdomiossarcoma/virologia , Ribavirina/farmacologia
12.
Nat Commun ; 11(1): 5253, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067459

RESUMO

Enterovirus 71 (EV71)-neutralizing antibodies correlate with protection and have potential as therapeutic agents. We isolate and characterize a panel of plasmablast-derived monoclonal antibodies from an infected child whose antibody response focuses on the plateau epitope near the icosahedral 3-fold axes. Eight of a total of 19 antibodies target this epitope and three of these potently neutralize the virus. Representative neutralizing antibodies 38-1-10A and 38-3-11A both confer effective protection against lethal EV71 challenge in hSCARB2-transgenic mice. The cryo-electron microscopy structures of the EV71 virion in complex with Fab fragments of these potent and protective antibodies reveal the details of a conserved epitope formed by residues in the BC and HI loops of VP2 and the BC and HI loops of VP3 spanning the region around the 3-fold axis. Remarkably, the two antibodies interact with the epitope in quite distinct ways. These plateau-binding antibodies provide templates for promising candidate therapeutics.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Enterovirus Humano A/imunologia , Infecções por Enterovirus/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Enterovirus Humano A/química , Enterovirus Humano A/genética , Infecções por Enterovirus/virologia , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização
13.
Arch Virol ; 165(12): 2909-2914, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32951133

RESUMO

Two and three genotypes of enterovirus G (EV-G) carrying a papain-like cysteine protease (PL-CP) sequence were detected on two pig farms and classified into genotypes G1 and G10, and G1, G8, and G17, respectively, based on VP1 sequences. A G10 EV-G virus bearing a PL-CP sequence was detected for the first time. Phylogenetic analysis of the P2 and P3 regions grouped the viruses by farm with high sequence similarity. Furthermore, clear recombination break points were detected in the 2A region, suggesting that PL-CP EV-G-containing strains gained sequence diversity through recombination events among the multiple circulating EV-G genotypes on the farms.


Assuntos
Cisteína Proteases/genética , Infecções por Enterovirus/veterinária , Enterovirus Suínos/genética , Genoma Viral , Recombinação Genética , Animais , Proteínas do Capsídeo/genética , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/virologia , Enterovirus Suínos/enzimologia , Fezes/virologia , Variação Genética , Genótipo , Japão , Filogenia , Análise de Sequência de DNA , Sus scrofa , Proteínas Virais/genética
14.
PLoS Pathog ; 16(9): e1008927, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32997711

RESUMO

Viruses cleave cellular proteins to remodel the host proteome. The study of these cleavages has revealed mechanisms of immune evasion, resource exploitation, and pathogenesis. However, the full extent of virus-induced proteolysis in infected cells is unknown, mainly because until recently the technology for a global view of proteolysis within cells was lacking. Here, we report the first comprehensive catalog of proteins cleaved upon enterovirus infection and identify the sites within proteins where the cleavages occur. We employed multiple strategies to confirm protein cleavages and assigned them to one of the two enteroviral proteases. Detailed characterization of one substrate, LSM14A, a p body protein with a role in antiviral immunity, showed that cleavage of this protein disrupts its antiviral function. This study yields a new depth of information about the host interface with a group of viruses that are both important biological tools and significant agents of disease.


Assuntos
Cisteína Endopeptidases/metabolismo , Infecções por Enterovirus/virologia , Enterovirus/patogenicidade , Replicação Viral/fisiologia , Antivirais/metabolismo , Enterovirus/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Proteólise , Proteínas Virais/metabolismo
15.
Nat Commun ; 11(1): 4775, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963221

RESUMO

Enterovirus 71 (EV71) poses serious threats to human health, particularly in Southeast Asia, and no drugs or vaccines are available. Previous work identified the stem loop II structure of the EV71 internal ribosomal entry site as vital to viral translation and a potential target. After screening an RNA-biased library using a peptide-displacement assay, we identify DMA-135 as a dose-dependent inhibitor of viral translation and replication with no significant toxicity in cell-based studies. Structural, biophysical, and biochemical characterization support an allosteric mechanism in which DMA-135 induces a conformational change in the RNA structure that stabilizes a ternary complex with the AUF1 protein, thus repressing translation. This mechanism is supported by pull-down experiments in cell culture. These detailed studies establish enterovirus RNA structures as promising drug targets while revealing an approach and mechanism of action that should be broadly applicable to functional RNA targeting.


Assuntos
Enterovirus Humano A/genética , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Interações Hospedeiro-Patógeno/fisiologia , Sítios Internos de Entrada Ribossomal/fisiologia , Replicação Viral/fisiologia , Regiões 5' não Traduzidas , Linhagem Celular , Infecções por Enterovirus/virologia , Regulação Viral da Expressão Gênica , Ribonucleoproteína Nuclear Heterogênea D0/metabolismo , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , RNA Viral/química , Proteínas Virais/metabolismo
16.
PLoS One ; 15(8): e0237652, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841272

RESUMO

EV-B93 is a novel serotype within the Enterovirus B species and is uncommon worldwide. Currently, only one full-length genomic sequence (the prototype strain) has been deposited in the GenBank database. In this study, three EV-B93 were identified, including one from an acute flaccid paralysis (AFP) patient (named 99052/XZ/CHN/1999, hereafter XZ99052) and two from healthy children (named 99096/XZ/CHN/1999 and 99167/XZ/CHN/1999, hereafter XZ99096 and XZ99167, respectively) from Tibet in 1999 during the polio eradication program. The identity between the nucleotide and amino acid sequences of the Tibet EV-B93 strain and the EV-B93 prototype strain is 83.2%-83.4% and 96.8%-96.9%, respectively. The Tibet EV-B93 strain was found to have greater nucleotide sequence identity in the P3 region to another enterovirus EV-B107 as per a phylogenetic tree analysis, which revealed that recombination occurred. Seroepidemiology data showed that EV-B93 has not produced an epidemic in Tibet and there may be susceptible individuals. The three Tibet EV-B93 strains are temperature-resistant with prognosticative virulence, suggesting the possibility of a potential large-scale outbreak of EV-B93. The analyzed EV-B93 strains enrich our knowledge about this serotype and provide valuable information on global EV-B93 molecular epidemiology. What is more, they permit the appraisal of the serotype's potential public health impact and aid in understanding the role of recombination events in the evolution of enteroviruses.


Assuntos
Enterovirus Humano B/genética , Infecções por Enterovirus/virologia , Genoma Viral/genética , Paralisia/virologia , Pré-Escolar , Surtos de Doenças/prevenção & controle , Enterovirus Humano B/isolamento & purificação , Enterovirus Humano B/patogenicidade , Infecções por Enterovirus/epidemiologia , Fezes/virologia , Feminino , Humanos , Lactente , Masculino , Tipagem Molecular , Paralisia/epidemiologia , Filogenia , RNA Viral/genética , Recombinação Genética , Análise de Sequência de RNA , Estudos Soroepidemiológicos , Tibet/epidemiologia
17.
PLoS Negl Trop Dis ; 14(8): e0008544, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804980

RESUMO

Hand, foot and mouth disease (HFMD) continues to challenge Asia with pandemic potential. In Vietnam, there have been two major outbreaks occurring during 2011-2012 (>200,000 hospitalizations and >200 deaths) and more recently in 2018 (>130,000 hospitalizations and 17 deaths). Given the high burden and the complex epidemic dynamics of HFMD, synthesizing its clinical and epidemiological data remains essential to inform the development of appropriate interventions and design public health measures. We report the results of a hospital-based study conducted during 2015-2018, covering the severe HFMD outbreak recently documented in Vietnam in 2018. The study was conducted at three major hospitals responsible for receiving HFMD patients from southern Vietnam with a population of over 40 million. A total of 19 enterovirus serotypes were detected in 1196 HFMD patients enrolled in the clinical study during 2015-2018, with enterovirus A71 (EV-A71), coxsackievirus A6 (CV-A6), CV-A10 and CV-A16 being the major causes. Despite the emergence of coxsackieviruses, EV-A71 remains the leading cause of severe HFMD in Vietnam. EV-A71 was consistently detected at a higher frequency during the second half of the years. The emergence of EV-A71 subgenogroup C4 in late 2018 was preceded by its low activity during 2017-early 2018. Compared with EV-A71 subgenogroup B5, C4 was more likely to be associated with severe HFMD, representing the first report demonstrating the difference in clinical severity between subgenogroup C4 and B5, the two predominant EV-A71 subgenogroups causing HFMD worldwide. Our data have provided significant insights into important aspects of HFMD over four years (2015-2018) in Vietnam, and emphasize active surveillance for pathogen circulation remains essential to inform the local public health authorities in the development of appropriate intervention strategies to reduce the burden of this emerging infections. Multivalent vaccines are urgently needed to control HFMD.


Assuntos
Doença de Mão, Pé e Boca/diagnóstico , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/etiologia , Criança , Pré-Escolar , Surtos de Doenças , Enterovirus/isolamento & purificação , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/etiologia , Infecções por Enterovirus/virologia , Feminino , Doença de Mão, Pé e Boca/virologia , Humanos , Lactente , Masculino , Sorogrupo , Vietnã/epidemiologia
18.
Arch Virol ; 165(11): 2531-2540, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32851429

RESUMO

Enterovirus 71 (EV71)-induced T lymphocyte apoptosis plays an important role in hand, foot, and mouth disease (HFMD), and granzyme B (GZMB) has been shown to be critical for this process. However, the mechanisms underlying GZMB-mediated apoptosis of T lymphocytes remain unknown. In this study, we investigated whether transcription factors and microRNAs (miRNAs) are involved in GZMB-mediated apoptosis of T lymphocytes in response to EV71 infection. Our findings indicated that EV71 infection significantly induced apoptosis in Jurkat cells, a human T lymphocytes cell line, as revealed in flow cytometric analysis. Furthermore, EV71 increased the expression of pro-apoptosis Bcl-2-associated X (Bax) and cleaved caspase 3 but decreased the expression of anti-apoptosis B-cell lymphoma protein 2 (Bcl2). GZMB knockdown decreased cell apoptosis and prevented EV71-induced changes in the expression of Bax, cleaved caspase 3, and Bcl2 in Jurkat cells, highlighting the role of GZMB as a key factor in EV71-induced apoptosis. Our study also indicated that overexpression of the transcription factors GATA binding factor 1 (GATA1) and specificity protein 1 (SP1) significantly increased luciferase activity when this gene was inserted in the GZMB 3' untranslated region (3'UTR). GATA1/SP1 overexpression induced cell apoptosis, increased the expression of Bax and cleaved caspase 3, and decreased the expression of Bcl2. Finally, our results suggested that miR-874 plays an essential role in GZMB-mediated cell apoptosis, since an miR-874 mimic decreases the expression of GZMB by targeting its 3'UTR. Collectively, these data indicated that GATA1/SP1 and miR-874 mediate EV71-induced apoptosis in a granzyme B-dependent manner. This signaling pathway may provide a new pharmacological target for the prevention and treatment of HFMD.


Assuntos
Enterovirus Humano A/genética , Infecções por Enterovirus/virologia , Fator de Transcrição GATA1/metabolismo , Granzimas/metabolismo , MicroRNAs/metabolismo , Fator de Transcrição Sp1/metabolismo , Apoptose , Caspase 3/imunologia , Enterovirus Humano A/fisiologia , Humanos , Células Jurkat , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
19.
Arch Virol ; 165(11): 2627-2632, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32776175

RESUMO

Due to the risk of poliovirus importation from Ukraine in 2015, a combined surveillance program monitoring the circulation of enteroviruses (EVs) in healthy children from at-risk areas and in the environment was conducted in Romania. Virological testing of stool samples collected from 155 healthy children aged from two months to six years and of 186 sewage water samples collected from different areas was performed. A total of 58 (37.42%) stool samples and 50 (26.88%) sewage water samples were positive for non-polio EVs, but no poliovirus was detected. A high level of circulation of echovirus (E) types 6 and 7 and coxsackievirus (CV) type B5 was observed.


Assuntos
Enterovirus Humano B/isolamento & purificação , Enterovirus/isolamento & purificação , Fezes/virologia , Esgotos/virologia , Criança , Pré-Escolar , Enterovirus/classificação , Enterovirus/genética , Enterovirus Humano B/genética , Infecções por Enterovirus/virologia , Meio Ambiente , Monitoramento Ambiental/métodos , Voluntários Saudáveis , Humanos , Lactente , Limite de Detecção , Modelos Logísticos , Tipagem Molecular/métodos , Filogenia , Poliovirus/genética , Poliovirus/isolamento & purificação , Romênia , Águas Residuárias/virologia
20.
Virology ; 548: 213-225, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32763492

RESUMO

The alteration of host cell splicing is a major strategy favouring viral replication; however, the interaction between human tonsillar epithelial cells (HTECs) and enterovirus 71 (EV71) has not been fully elucidated. Here, a total of 201 differentially expressed genes (DEGs) and 3266 novel genes with coding potential were identified. A total of 3479 skipped exons (SEs), 515 alternative 3' splice sites (A3SSs), 391 alternative 5' splice sites (A5SSs), 531 mutually exclusive exons (MXEs) and 825 retained introns (RIs) were identified as significantly altered alternative splicing (AS) events. The enriched DEGs were mainly related to the cell cycle, spliceosome, and Toll-like receptor (TLR) signalling pathways. Finally, the replication of EV71 was significantly inhibited by TLR2 heterodimers. Our findings suggest that AS events induced by EV71 increase the transcriptomic diversity of HTECs in response to EV71 infection. Additionally, TLR2 heterodimers have the potential to protect HTECs against EV71.


Assuntos
Enterovirus Humano A/fisiologia , Infecções por Enterovirus/genética , Processamento Alternativo , Enterovirus Humano A/genética , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno , Humanos , Sítios de Splice de RNA , Transcriptoma
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