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1.
BMC Public Health ; 22(1): 1483, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927656

RESUMO

BACKGROUND: Enterovirus A71 (EV A71) is one of the most important enteroviruses related to morbidity and mortality in children worldwide. This study aimed to analyse the secular trend of EV A71 in Taiwan from 1998 to 2020 and to evaluate the effectiveness of infection control measures. METHODS: We collected the epidemiological data of EV A71 from disease surveillance systems in Taiwan. We analysed the association between the secular trend of EV A71 and preventive measures such as hand washing, case isolation, and suspension of classes. RESULTS: The incidence of enterovirus infections with severe complications (EVSC) decreased from 16.25 per 100,000 children under six in 1998 to less than 9.73 per 100,000 children under six after 2012 (P = 0.0022). The mortality rate also decreased significantly, from 3.52 per 100,000 children under six in 1998 to 0 per 100,000 children under six in 2020 (P < 0.0001). The numbers of EVSC and fatalities were significantly higher in the years when EV A71 accounted for more than 10% of the annual predominant serotypes (p < 0.05). After the implementation of many non-pharmaceutical interventions in 2012, the incidence of EVSC and mortality rate decreased significantly (p < 0.001). CONCLUSIONS: After implementing active enterovirus surveillance and preventive measures, we found that the incidence of EVSC and fatalities due to EV A71 in Taiwan decreased significantly from 1998 to 2020. Continuous surveillance and strengthened infection control policies are still needed in the future.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Criança , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/prevenção & controle , Humanos , Sorogrupo , Taiwan/epidemiologia
2.
Front Cell Infect Microbiol ; 12: 941325, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909978

RESUMO

Enterovirus A (EV-A) species cause hand, foot and mouth disease (HFMD), threatening the health of young children. Understanding the mutual codon usage pattern of the virus and its host(s) has fundamental and applied values. Here, through examining multiple codon usage parameters, we found that the codon usage bias among EV-A strains varies and is clade-specific. EVA76, EVA89, EVA90, EVA91 and EVA92, the unconventional clade of EV-A strains, show unique codon usage pattern relative to the two conventional clades, including EVA71, CVA16, CVA6 and CVA10, etc. Analyses of Effective Number of Codon (ENC), Correspondence Analysis (COA) and Parity Rule 2 (PR2), etc., revealed that the codon usage patterns of EV-A strains are shaped by mutation pressure and natural selection. Based on the neutrality analysis, we determined the dominant role of natural selection in the formation of the codon usage bias of EV-A. In addition, we have determined the codon usage compatibility of potential hosts for EV-A strains using codon adaptation index (CAI), relative codon deoptimization index (RCDI) and similarity index (SiD) analyses, and found that EV-A showed host-specific codon adaptation patterns in different clades. Finally, we confirmed that the unique codon usage pattern of the unconventional clade affected protein expression level in human cell lines. In conclusion, we identified novel characteristics of codon usage bias in distinct EV-A clades associated with their host range, transmission and pathogenicity.


Assuntos
Infecções por Enterovirus , Enterovirus , Antígenos Virais , Criança , Pré-Escolar , Códon , Uso do Códon , Infecções por Enterovirus/genética , Evolução Molecular , Humanos , Filogenia , Seleção Genética
3.
BMC Infect Dis ; 22(1): 671, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927711

RESUMO

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a common child infectious disease caused by more than 20 enterovirus (EV) serotypes. In recent years, enterovirus A71 (EV-A71) has been replaced by Coxsackievirus A6 (CV-A6) to become the predominant serotype. Multiple EV serotypes co-circulate in HFMD epidemics, and this study aimed to investigate the etiological epidemic characteristics of an HFMD outbreak in Kunming, China in 2019. METHODS: The clinical samples of 459 EV-associated HFMD patients in 2019 were used to amplify the VP1 gene region by the three sets of primers and identify serotypes using the molecular biology method. Phylogenetic analyses were performed based on the VP1 gene. RESULTS: Three hundred and forty-eight cases out of 459 HFMD patients were confirmed as EV infection. Of these 191 (41.61%) were single EV infections and 34.20% had co-infections. The EVs were assigned to 18 EV serotypes, of which CV-A6 was predominant (11.33%), followed by CV-B1 (8.93%), CV-A4 (5.23%), CV-A9 (4.58%), CV-A 16 (3.49%) and CV-A10 and CVA5 both 1.96%. Co-infection of CV-A6 with other EVs was present in 15.25% of these cases, followed by co-infection with CV-A16 and other EVs. The VP1 sequences used in the phylogenetic analyses showed that the CV-A6, CV-B1 and CV-A4 sequences belonged to the sub-genogroup D3 and genogroups F and E, respectively. CONCLUSION: Co-circulation and co-infection of multiple serotypes were the etiological characteristic of the HFMD epidemic in Kunming China in 2019 with CV-A-6, CV-B1 and CV-A4 as the predominant serotypes. This is the first report of CV-B1 as a predominant serotype in China and may provide valuable information for the diagnosis, prevention and control of HFMD.


Assuntos
Coinfecção , Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Criança , China/epidemiologia , Coinfecção/epidemiologia , Enterovirus/genética , Enterovirus Humano B , Infecções por Enterovirus/epidemiologia , Doença de Mão, Pé e Boca/epidemiologia , Humanos , Lactente , Vacinação em Massa , Filogenia
4.
Front Immunol ; 13: 943334, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935957

RESUMO

Interferons (IFN) are antiviral cytokines with critical roles in regulating pathogens at epithelial barriers, but their capacity to restrict human enteric viruses has been incompletely characterized in part due to challenges in cultivating some viruses in vitro, particularly human norovirus. Accordingly, advancements in the development of antiviral therapies and vaccine strategies for enteric viral infections have been similarly constrained. Currently emerging is the use of human intestinal enteroids (HIEs) to investigate mechanisms of human enteric viral pathogenesis. HIEs provide a unique opportunity to investigate host-virus interactions using an in vitro system that recapitulates the cellular complexity of the in vivo gastrointestinal epithelium. This approach permits the exploration of intestinal epithelial cell interactions with enteric viruses as well as the innate immune responses mediated by IFNs and IFN-stimulated genes. Here, we describe recent findings related to the production, signaling, and function of IFNs in the response to enteric viral infections, which will ultimately help to reveal important aspects of pathogenesis and facilitate the future development of therapeutics and vaccines.


Assuntos
Infecções por Enterovirus , Enterovirus , Antivirais , Humanos , Imunidade Inata , Interferons , Organoides
5.
BMC Public Health ; 22(1): 1468, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35915424

RESUMO

BACKGROUND: The enterovirus 71 (EV-A71) vaccine has been used in Hefei for several years, and the epidemiological significance of vaccination in this area is unclear. We aims to explore the spatial-temporal-demographic and virological changes of hand, foot and mouth disease (HFMD) after vaccination in China. METHODS: The data for HFMD from 2012 to 2020 were downloaded with the help of HFMD reporting system of Hefei Center for Disease Control and Prevention and combined with the EV-A71 vaccination status in Hefei. The study defined the period between 2012 to 2016 as the pre-vaccination period and explored the effect of vaccination on the incidence of HFMD by comparing the changes of HFMD before and after vaccination in terms of spatial, temporal, demographic and virological aspects. RESULTS: During the study period, a higher incidence occurred in urban area and the random distribution changed to a slight cluster after vaccination. HFMD incidence had inconsistent seasonality over years, with one or two incidence peaks in varying years. The morbidity decreased from 215.22/105 in 2012-2016 to 179.81/105 in 2017-2020 (p < 0.001). Boys, 0-4 years old children and Scattered children were more susceptible to HFMD compared with the others, the proportions decreased after vaccination except in Scattered children. The main pathogenic enterovirus gradually changed from EV-A71 to Other Enteroviruses, especially coxsackieviruses A6 (CV-A6) after the implementation of EV-A71 vaccination. CONCLUSIONS: The EV-A71 vaccine was effective in reducing the incidence of HFMD and changing the spatial, temporal, demographic, and virological characteristic. These changes should be considered during the vaccination implementation to further reduce the disease burden of HFMD.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Criança , Pré-Escolar , China/epidemiologia , Infecções por Enterovirus/epidemiologia , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/prevenção & controle , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Vacinação
6.
Artigo em Inglês | MEDLINE | ID: mdl-35805367

RESUMO

Enteric viruses (EVs) occurrence within aquatic environments varies and leads to significant risk on public health of humans, animals, and diversity of aquatic taxa. Early and efficacious recognition of cultivable and fastidious EVs in aquatic systems are important to ensure the sanitary level of aquatic water and implement required treatment strategies. Herein, we provided a comprehensive overview of the conventional and up-to-date eco-genomic tools for aquatic biomonitoring of EVs, aiming to develop better water pollution monitoring tools. In combination with bioinformatics techniques, genetic tools including cloning sequencing analysis, DNA microarray, next-generation sequencing (NGS), and metagenomic sequencing technologies are implemented to make informed decisions about the global burden of waterborne EVs-associated diseases. The data presented in this review are helpful to recommend that: (1) Each viral pollution detection method has its own merits and demerits; therefore, it would be advantageous for viral pollution evaluation to be integrated as a complementary platform. (2) The total viral genome pool extracted from aquatic environmental samples is a real reflection of pollution status of the aquatic eco-systems; therefore, it is recommended to conduct regular sampling through the year to establish an updated monitoring system for EVs, and quantify viral peak concentrations, viral typing, and genotyping. (3) Despite that conventional detection methods are cheaper, it is highly recommended to implement molecular-based technologies to complement aquatic ecosystems biomonitoring due to numerous advantages including high-throughput capability. (4) Continuous implementation of the eco-genetic detection tools for monitoring the EVs in aquatic ecosystems is recommended.


Assuntos
Ecossistema , Enterovirus , Animais , Monitoramento Biológico , Enterovirus/genética , Monitoramento Ambiental/métodos , Genoma Viral , Metagenômica/métodos , Microbiologia da Água
7.
Molecules ; 27(13)2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35807341

RESUMO

Biotransformation of specific saponins in the valuable medical plants to increase their bioavailability and pharmaceutical activities has attracted more and more attention. A gene encoding a thermophilic glycoside hydrolase from Fervidobaterium pennivorans DSM9078 was cloned and expressed in Escherichia coli. The purified recombinant enzyme, exhibiting endoglucanase cellulase activity, was used to transform gypenoside XLIX into gylongiposide I via highly selective and efficient hydrolysis of the glucose moiety linked to the C21 position in gypenoside XLIX. Under the optimal reaction conditions for large scale production of gylongiposide I, 35 g gypenoside XLIX was transformed by using 20 g crude enzyme at pH 6.0 and 80 °C for 4 h with a molar yield of 100%. Finally, 11.51 g of gylongiposide I was purified using a silica gel column with 91.84% chromatographic purity. Furthermore, inhibitory activities of gypenoside XLIX and gylongiposide I against Enterovirus 71 (EV71) were investigated. Importantly, the EC50 of gypenoside XLIX and gylongiposide I calculated from viral titers in supernatants was 3.53 µM and 1.53 µM, respectively. Moreover, the transformed product gylongiposide I has better anti-EV71 activity than the glycosylated precursor. In conclusion, this enzymatic method would be useful in the large-scale production of gylongiposide I, which would be a novel potent anti-EV71 candidate.


Assuntos
Enterovirus Humano A , Enterovirus , Saponinas , Antivirais/metabolismo , Antivirais/farmacologia , Biotransformação , Enterovirus/metabolismo , Gynostemma/química , Imidazóis , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Saponinas/química , Sulfonamidas , Tiofenos , Triterpenos
8.
Medicine (Baltimore) ; 101(26): e29772, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35777023

RESUMO

BACKGROUND: Viral infection is the most common cause of aseptic meningitis. The purpose of this study was to identify the viruses responsible for aseptic meningitis to better understand the clinical presentations of this disease. METHOD: Between March 2009 and February 2010, we collected 297 cerebrospinal fluid specimens from children with aseptic meningitis admitted to a pediatric hospital in Yunnan (China). Viruses were detected by using "in house" real-time quantitative polymerase chain reaction or reverse-transcription real-time quantitative polymerase chain reaction from these samples. Phylogenetic analyses were conducted using the Molecular Evolutionary Genetic Analysis version 7.0 software, with the neighbor-joining method. RESULTS: Viral infection was diagnosed in 35 of the 297 children (11.8%). The causative viruses were identified to be enteroviruses in 25 cases (71.4%), varicella-zoster virus in 5 cases (14.3%), herpes simplex virus 1 in 2 cases (5.7%), and herpes simplex virus 2, Epstein-Barr virus, and human herpesvirus 6 in 1 case each (2.9% each). Of the enteroviruses, coxsackievirus B5 was the most frequently detected serotype (10/25 cases; 40.0%) and all coxsackievirus B5 strains belonged to C group. CONCLUSIONS: In the study, a causative virus was only found in the minority of cases, of them, enteroviruses were the most frequently detected viruses in patients with viral meningitis, followed by varicella-zoster virus and herpes simplex virus. Our findings underscore the need for enhanced surveillance and etiological study of aseptic meningitis.


Assuntos
Infecções por Enterovirus , Enterovirus , Infecções por Vírus Epstein-Barr , Meningite Asséptica , Meningite Viral , Vírus , Criança , China/epidemiologia , Enterovirus/genética , Infecções por Enterovirus/epidemiologia , Herpesvirus Humano 2 , Herpesvirus Humano 3 , Herpesvirus Humano 4 , Humanos , Meningite Asséptica/líquido cefalorraquidiano , Meningite Asséptica/epidemiologia , Meningite Asséptica/etiologia , Meningite Viral/diagnóstico , Filogenia
9.
Vopr Virusol ; 67(3): 185-192, 2022 07 13.
Artigo em Russo | MEDLINE | ID: mdl-35831961

RESUMO

Non-polio enteroviruses (NPEVs) are ubiquitous and are one of the main causative agents of viral infections in children. NPEVs most commonly infect newborns and young children, due to their lack of antibodies. In children, clinical manifestations can range from acute febrile illness to severe complications that require hospitalization and lead in some cases to disability or death. NPEV infections can have severe consequences, such as polio-like diseases, serous meningitis, meningoencephalitis, myocarditis, etc. The most promising strategy for preventing such diseases is vaccination. No less than 53 types of NPEVs have been found to circulate in Russia. However, of epidemic importance are the causative agents of exanthemic forms of the disease, aseptic meningitis and myocarditis. At the same time, the frequency of NPEV detection in the constituent entities of the Russian Federation is characterized by uneven distribution and seasonal upsurges. The review discusses the epidemic significance of different types of enteroviruses, including those relevant to the Russian Federation, as well as current technologies used to create enterovirus vaccines for the prevention of serious diseases.


Assuntos
Infecções por Enterovirus , Enterovirus , Miocardite , Picornaviridae , Vacinas , Criança , Pré-Escolar , Enterovirus/genética , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/prevenção & controle , Humanos , Recém-Nascido
10.
Viruses ; 14(8)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35893665

RESUMO

We describe the genesis of poliovirus (PV) and non-polio enterovirus (NPEV) surveillance program of sewage wastewaters from its inception to the present in the Slovak Republic (SR). Sampling procedures and evolution of the methodology used in the SR for the detection of PVs and NPEVs are presented chronologically. For statistical data processing, we divided our dataset into two periods, the first period from 1963 to 1998 (35 years), and the second period from 1999 to 2019 (21 years). Generalized additive models were used to assess temporal trends in the probability of occurrence of major EV serotypes during both periods. Canonical correspondence analysis on relative abundance data was used to test temporal changes in the composition of virus assemblages over the second period. The probability of occurrence of major viruses PV, coxsackieviruses (CVA, CVB), and Echoviruses (E)) significantly changed over time. We found that 1015 isolated PVs were of vaccine origin, called "Sabin-like" (isolates PV1, PV2, PV3). The composition of EV assemblages changed significantly during the second period. We conclude that during the whole period, CVB5, CVB4, and E3 were prominent NPEVS in the SR.


Assuntos
Infecções por Enterovirus , Enterovirus , Poliovirus , Antígenos Virais , Infecções por Enterovirus/epidemiologia , Humanos , Eslováquia/epidemiologia , Águas Residuárias
11.
Artigo em Inglês | MEDLINE | ID: mdl-35886521

RESUMO

Irradiation with ultraviolet light (UV) at 254 nm is effective in inactivating a wide range of human pathogens. In Sweden, a UV dose of 400 J/m2 is often used for the treatment of drinking water. To investigate its effect on virus inactivation, enteric viruses with different genomic organizations were irradiated with three UV doses (400, 600, and 1000 J/m2), after which their viability on cell cultures was examined. Adenovirus type 2 (double-stranded DNA), simian rotavirus 11 (double-stranded RNA), and echovirus 30 (single-stranded RNA) were suspended in tap water and pumped into a laboratory-scale Aquada 1 UV reactor. Echovirus 30 was reduced by 3.6-log10 by a UV dose of 400 J/m2. Simian rotavirus 11 and adenovirus type 2 were more UV resistant with only 1-log10 reduction at 400 J/m2 and needed 600 J/m2 for 2.9-log10 and 3.1-log10 reductions, respectively. There was no significant increase in the reduction of viral viability at higher UV doses, which may indicate the presence of UV-resistant viruses. These results show that higher UV doses than those usually used in Swedish drinking water treatment plants should be considered in combination with other barriers to disinfect the water when there is a risk of fecal contamination of the water.


Assuntos
Água Potável , Enterovirus , Rotavirus , Purificação da Água , Adenoviridae/genética , Desinfecção/métodos , Humanos , Suécia , Raios Ultravioleta , Inativação de Vírus/efeitos da radiação , Purificação da Água/métodos
12.
PLoS Pathog ; 18(7): e1010632, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35789345

RESUMO

Enteroviruses (EVs) are among the most prevalent viruses worldwide. They are characterized by a high genetic and phenotypic diversity, being able to cause a plethora of symptoms. EV-D68, a respiratory EV, and EV-D94, an enteric EV, represent an interesting paradigm of EV tropism heterogeneity. They belong to the same species, but display distinct phenotypic characteristics and in vivo tropism. Here, we used these two viruses as well as relevant 3D respiratory, intestinal and neural tissue culture models, to highlight key distinctive features of enteric and respiratory EVs. We emphasize the critical role of temperature in restricting EV-D68 tissue tropism. Using transcriptomic analysis, we underscore fundamental differences between intestinal and respiratory tissues, both in the steady-state and in response to infection. Intestinal tissues present higher cell proliferation rate and are more immunotolerant than respiratory tissues. Importantly, we highlight the different strategies applied by EV-D94 and EV-D68 towards the host antiviral response of intestinal and respiratory tissues. EV-D68 strongly activates antiviral pathways while EV-D94, on the contrary, barely induces any host defense mechanisms. In summary, our study provides an insightful characterization of the differential pathogenesis of EV-D68 and EV-D94 and the interplay with their main target tissues.


Assuntos
Enterovirus Humano D , Infecções por Enterovirus , Enterovirus , Infecções Respiratórias , Antígenos Virais , Antivirais , Enterovirus Humano D/fisiologia , Humanos , Tropismo
13.
Molecules ; 27(13)2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35807435

RESUMO

Enterovirus 71 (EV71) is a dominant pathogenic agent that may cause severe central nervous system (CNS) diseases among infants and young children in the Asia-pacific. The inflammasome is closely implicated in EV71-induced CNS injuries through a series of signaling pathways. However, the activation pathway of NLRP3 inflammasome involved in EV71-mediated CNS injuries remains poorly defined. In the studies, EV71 infection, ERK1/2 phosphorylation, and activation of NLRP3 are abolished in glioblastoma cells with low vimentin expression by CRISPR/Cas9-mediated knockdown. PD098059, an inhibitor of p-ERK, remarkably blocks the vimentin-mediated ERK1/2 phosphorylation in EV71-infected cells. Nuclear translocation of NF-κB p65 is dependent on p-ERK in a time-dependent manner. Moreover, NLRP3 activation and caspase-1 production are limited in EV71-infected cells upon the caffeic acid phenethyl ester (CAPE) administration, an inhibitor of NF-κB, which contributes to the inflammasome regulation. In conclusion, these results suggest that EV71-mediated NLRP3 inflammasome could be activated via the VIM-ERK-NF-κB pathway, and the treatment of the dephosphorylation of ERK and NF-κB inhibitors is beneficial to host defense in EV71-infected CNS.


Assuntos
Enterovirus , Glioblastoma , NF-kappa B , Vimentina , Criança , Pré-Escolar , Enterovirus/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/virologia , Humanos , Inflamassomos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fosforilação , Vimentina/genética , Vimentina/metabolismo
14.
Virology ; 573: 167-175, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35834888

RESUMO

A prototype strain of Coxsackievirus A21 (CVA21) is under clinical evaluation as an oncolytic virus immunotherapy. To improve scalability of the manufacturing process, an affinity chromatography purification method was developed using immobilized glutathione resin that captured infectious CVA21 virions from cell culture harvests with high recovery and impurity clearance. Unexpectedly, the binding of empty CVA21 procapsids depended on production cell culture conditions during infection including temperature, presence of serum in the media, and production cell line. At 37 °C and 2% serum during infection, procapsids flowed-through while infectious virions bound and were recovered at >95% yield in the chromatography elution. However, at sub-physiological temperature or after removal of serum at infection, both procapsids and mature virions bound and co-eluted from the immobilized glutathione ligand. This work may improve the understanding of CVA21 capsid assembly and presents an efficient purification method that may be applied to picornaviruses that interact with intracellular GSH.


Assuntos
Enterovirus Humano A , Enterovirus , Vírus Oncolíticos , Capsídeo/metabolismo , Técnicas de Cultura de Células , Enterovirus Humano A/metabolismo , Glutationa/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Vírus Oncolíticos/metabolismo
15.
Viruses ; 14(8)2022 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-35893676

RESUMO

TRIM7 catalyzes the ubiquitination of multiple substrates with unrelated biological functions. This cross-reactivity is at odds with the specificity usually displayed by enzymes, including ubiquitin ligases. Here we show that TRIM7's extreme substrate promiscuity is due to a highly unusual binding mechanism, in which the PRYSPRY domain captures any ligand with a C-terminal helix that terminates in a hydrophobic residue followed by a glutamine. Many of the non-structural proteins found in RNA viruses contain C-terminal glutamines as a result of polyprotein cleavage by 3C protease. This viral processing strategy generates novel substrates for TRIM7 and explains its ability to inhibit Coxsackie virus and norovirus replication. In addition to viral proteins, cellular proteins such as glycogenin have evolved C-termini that make them a TRIM7 substrate. The 'helix-ΦQ' degron motif recognized by TRIM7 is reminiscent of the N-end degron system and is found in ~1% of cellular proteins. These features, together with TRIM7's restricted tissue expression and lack of immune regulation, suggest that viral restriction may not be its physiological function.


Assuntos
Infecções por Caliciviridae , Glutamina , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Proteases Virais 3C , Enterovirus , Humanos , Norovirus , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/genética
16.
Sci Rep ; 12(1): 12846, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896602

RESUMO

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease associated with neurological complications in young children. Currently, there is no specific treatment for EV-A71 infection due to the inadequate information on viral biology and neuropathogenesis. Among enteroviruses, nonstructural 3A protein mediates the formation of replication organelles which plays a major role in viral RNA synthesis and assembly. Although enteroviral 3A proteins have been intensively studied, the data on EV-A71 3A, especially in neuronal cells, are still limited. In this study, PRSS3 (mesotrypsinogen, also known as brain trypsinogen) was identified as EV-A71 3A-interacting counterpart from the transfected human neuroblastoma SH-SY5Y cells by pull-down assay and liquid chromatography tandem mass spectrometry. It was confirmed that PRSS3 variant 3 derived from human SH-SY5Y cells had the physical interaction with EV-A71 3A. Importantly, the role of PRSS3 in EV-A71 replication was verified by overexpression and siRNA-mediated gene silencing approaches. The detailed mechanism of the PRSS3 involved in EV-A71 replication and neuropathogenesis warrants further experimental elucidation. In conclusion, this study has discovered a novel EV-A71 3A interacting protein that offers the opportunity to study the neuropathogenesis of the infection which paves the way for developing a specific and effective treatment for the disease.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Neuroblastoma , Antígenos Virais , Criança , Pré-Escolar , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/metabolismo , Humanos , Proteínas , Tripsina , Replicação Viral/fisiologia
17.
Viruses ; 14(7)2022 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-35891342

RESUMO

Enterovirus 2Apro is a protease that proteolytically processes the viral polyprotein and cleaves several host proteins to antagonize host responses during enteroviral infection. Recently, the host protein actin histidine methyltransferase SET domain containing 3 (SETD3) was identified to interact with 2Apro and to be essential for virus replication. The role of SETD3 and its interaction with 2Apro remain unclear. In this study, we investigated the potential involvement of SETD3 in several functions of 2Apro. For this, we introduced the 2Apro from coxsackievirus B3 (CVB3) in a mutant of encephalomyocarditis virus (EMCV) containing an inactivated Leader protein (EMCV-Lzn) that is unable to shut down host mRNA translation, to trigger nucleocytoplasmic transport disorder (NCTD), and to suppress stress granule (SG) formation and type I interferon (IFN) induction. Both in wt HeLa cells and in HeLa SETD3 knockout (SETD3KO) cells, the virus containing active 2Apro (EMCV-2Apro) efficiently cleaved eukaryotic translation initiation factor 4 gamma (eIF4G) to shut off host mRNA translation, cleaved nucleoporins to trigger NCTD, and actively suppressed SG formation and IFN gene transcription, arguing against a role of SETD3 in these 2Apro-mediated functions. Surprisingly, we observed that the catalytic activity of enteroviral 2A is not crucial for triggering NCTD, as a virus containing an inactive 2Apro (EMCV-2Am) induced NCTD in both wt and SETD3KO cells, albeit delayed, challenging the idea that the NCTD critically depends on nucleoporin cleavage by this protease. Taken together, our results do not support a role of SETD3 in the proteolytic activities of enterovirus 2Apro.


Assuntos
Infecções por Enterovirus , Enterovirus , Antígenos Virais/metabolismo , Vírus da Encefalomiocardite/genética , Enterovirus/genética , Células HeLa , Histona Metiltransferases/metabolismo , Humanos , Peptídeo Hidrolases/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo
18.
J Immunol ; 209(2): 280-287, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35777850

RESUMO

Hand, foot, and mouth disease (HFMD), which is mainly caused by coxsackievirus A16 (CVA16) or enterovirus A71 (EV-A71), poses a serious threat to children's health. However, the long-term dynamics of the neutralizing Ab (NAb) response and ideal paired-serum sampling time for serological diagnosis of CVA16-infected HFMD patients were unclear. In this study, 336 CVA16 and 253 EV-A71 PCR-positive HFMD inpatients were enrolled and provided 452 and 495 sera, respectively, for NAb detection. Random-intercept modeling with B-spline was conducted to characterize NAb response kinetics. The NAb titer of CVA16 infection patients was estimated to increase from negative (2.1, 95% confidence interval [CI]: 1.4-3.3) on the day of onset to a peak of 304.8 (95% CI: 233.4-398.3) on day 21 and then remained >64 until 26 mo after onset. However, the NAb response level of EV-A71-infected HFMD patients was much higher than that of CVA16-infected HFMD patients throughout. The geometric mean titer was significantly higher in severe EV-A71-infected patients than in mild patients, with a 2.0-fold (95% CI: 1.4-3.2) increase. When a 4-fold rise in titer was used as the criterion for serological diagnosis of CVA16 and EV-A71 infection, acute-phase serum needs to be collected at 0-5 d, and the corresponding convalescent serum should be respectively collected at 17.4 (95% CI: 9.6-27.4) and 24.4 d (95% CI: 15.3-38.3) after onset, respectively. In conclusion, both CVA16 and EV-A71 infection induce a persistent humoral immune response but have different NAb response levels and paired-serum sampling times for serological diagnosis. Clinical severity can affect the anti-EV-A71 NAb response.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Anticorpos Neutralizantes , Criança , China/epidemiologia , Estudos de Coortes , Doença de Mão, Pé e Boca/diagnóstico , Humanos , Lactente , Estudos Longitudinais
19.
mBio ; 13(3): e0085422, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35652592

RESUMO

For RNA virus families except Picornaviridae, viral RNA sensing includes Toll-like receptors and/or RIG-I. Picornavirus RNAs, whose 5' termini are shielded by a genome-linked protein, are predominately recognized by MDA5. This has important ramifications for adaptive immunity, as MDA5-specific patterns of type-I interferon (IFN) release are optimal for CD4+T cell TH1 polarization and CD8+T cell priming. We are exploiting this principle for cancer immunotherapy with recombinant poliovirus (PV), PVSRIPO, the type 1 (Sabin) PV vaccine containing a rhinovirus type 2 internal ribosomal entry site (IRES). Here we show that PVSRIPO-elicited MDA5 signaling is preceded by early sensing of the IRES by the double-stranded (ds)RNA-activated protein kinase (PKR). PKR binding to IRES stem-loop domains 5-6 led to dimerization and autoactivation, displaced host translation initiation factors, and suppressed viral protein synthesis. Early PKR-mediated antiviral responses tempered incipient viral translation and the activity of cytopathogenic viral proteinases, setting up accentuated MDA5 innate inflammation in response to PVSRIPO infection. IMPORTANCE Among the RIG-I-like pattern recognition receptors, MDA5 stands out because it senses long dsRNA duplexes independent of their 5' features (RIG-I recognizes viral [v]RNA 5'-ppp blunt ends). Uniquely among RNA viruses, the innate defense against picornaviruses is controlled by MDA5. We show that prior to engaging MDA5, recombinant PV RNA is sensed upon PKR binding to the viral IRES at a site that overlaps with the footprint for host translation factors mediating 40S subunit recruitment. Our study demonstrates that innate antiviral type-I IFN responses orchestrated by MDA5 involve separate innate modules that recognize distinct vRNA features and interfere with viral functions at multiple levels.


Assuntos
Enterovirus , Poliovirus , Vírus de RNA , Antivirais , Enterovirus/genética , Imunidade Inata , Sítios Internos de Entrada Ribossomal , Poliovirus/genética , Vírus de RNA/genética , RNA de Cadeia Dupla , RNA Viral/genética , Receptores de Reconhecimento de Padrão/genética
20.
Microbiol Spectr ; 10(3): e0266221, 2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35652637

RESUMO

Most enterovirus (EV) infections are subclinical but, occasionally, can cause severe and potentially fatal diseases in humans and animals. Currently, EVs are divided into 12 types (A to L) based on phylogenetic analysis and on their natural hosts. Bovine enterovirus (BEV) is an essential member of the enterovirus belonging to the types E and F that attacks cattle as its natural host and causes clinical disorders in the digestive, respiratory, and reproductive tracts. In 2020, several dairy farms in China experienced cow mortality with acute clinical signs, including fever, and diarrhea. In these cases, GX20-1 and JS20-1 virus strains were isolated and sequenced. Cellular adaptation of these two strains showed efficient replications on Madin-Darby bovine kidney (MDBK) cells and produced a significant cytopathogenic effect (CPE). However, on baby hamster kidney (BHK-21) and Vero cells, viral replication was inefficient and did not produce CPE. As noted in comparative genomics analysis, these two strains showed distant evolutionary relationships with the well-known E1 to E4 and F1 to F4 subtypes of BEV and high sequence identities with the candidate type Enterovirus E5, a novel genotype recently identified based on the genomic data of three strains, including the GX20-1 and JS20-1 strains. This study provides the first evidence of a novel genotype bovine enterovirus infection in Chinese cattle herds, a potential threat to the cattle industry in China. IMPORTANCE Bovine enterovirus (BEV) is a cattle-infecting pathogen. This study is the first report of natural infection of a novel genotype of enterovirus in herds of cattle in China. The homology of the novel enterovirus is far different from the structural protein of other enteroviruses and has different cellular adaptations. This study provides a reference for the biological characteristics and prevalence of the novel enterovirus in Chinese cattle populations.


Assuntos
Infecções por Enterovirus , Enterovirus Bovino , Enterovirus , Animais , Bovinos , China/epidemiologia , Chlorocebus aethiops , Enterovirus/genética , Infecções por Enterovirus/epidemiologia , Infecções por Enterovirus/veterinária , Enterovirus Bovino/genética , Genoma Viral , Genótipo , Filogenia , Células Vero
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