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1.
Medicine (Baltimore) ; 98(33): e16493, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415349

RESUMO

RATIONALE: Unlike other enteroviruses which can cause herpangina or hand-foot-and-mouth disease, enterovirus D68 (EV-D68) has usually been linked to respiratory and neurological problems in young children. Skin manifestations had rarely been described in current literatures. PATIENT CONCERNS: We report a 17-year-old girl with fever and painful skin rash over legs and soles for 9 days. Pitting edema was also noted below the knees. There was no respiratory tract or neurological symptoms in this patient. DIAGNOSES: EV-D68 was detected from a throat swab by RT-PCR and confirmed to be subclade B3 by sequencing. INTERVENTIONS: Supportive management. OUTCOMES: The patient was afebrile after 9 days and got full recovery on the 23rd day at outpatient follow-up. LESSONS: To the best of our knowledge, this is the first report of EV-D68 infection with skin manifestations, clinical images, and detailed clinical course. Our findings in this particular case extend the understanding of the disease spectrum.


Assuntos
Dor Aguda/virologia , Enterovirus Humano D , Infecções por Enterovirus/virologia , Exantema/virologia , Dor Aguda/patologia , Adolescente , Infecções por Enterovirus/patologia , Exantema/patologia , Feminino , Humanos
2.
Nat Commun ; 10(1): 3171, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320648

RESUMO

Enteroviruses are a major cause of human disease. Adipose-specific phospholipase A2 (PLA2G16) was recently identified as a pan-enterovirus host factor and potential drug target. In this study, we identify a possible mechanism of PLA2G16 evasion by employing a dual glycan receptor-binding enterovirus D68 (EV-D68) strain. We previously showed that this strain does not strictly require the canonical EV-D68 receptor sialic acid. Here, we employ a haploid screen to identify sulfated glycosaminoglycans (sGAGs) as its second glycan receptor. Remarkably, engagement of sGAGs enables this virus to bypass PLA2G16. Using cryo-EM analysis, we reveal that, in contrast to sialic acid, sGAGs stimulate genome release from virions via structural changes that enlarge the putative openings for genome egress. Together, we describe an enterovirus that can bypass PLA2G16 and identify additional virion destabilization as a potential mechanism to circumvent PLA2G16.


Assuntos
Enterovirus Humano D/crescimento & desenvolvimento , Glicosaminoglicanos/metabolismo , Fosfolipases A2 Independentes de Cálcio/metabolismo , Receptores Virais/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Internalização do Vírus , Desenvelopamento do Vírus/fisiologia , Linhagem Celular Tumoral , Microscopia Crioeletrônica , Enterovirus Humano D/genética , Infecções por Enterovirus/patologia , Genoma Viral/genética , Células HEK293 , Células HeLa , Humanos , Ácido N-Acetilneuramínico/metabolismo
3.
Eur J Paediatr Neurol ; 23(2): 235-239, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30670331

RESUMO

Acute flaccid myelitis (AFM) was increasingly detected in recent years, coinciding with upsurges of enterovirus D68 (EV-D68) infections. We reviewed the evidence for a causal relationship between both. Based on reported cases, we provide case definitions for AFM caused by EV-D68 infections to enable a standard procedure for affected patients. Current case definitions are focussing on epidemiological aspects but clinical case definitions are still missing. We propose the following case definitions to be used in clinical practice in order to mirror clinical realities and facilitate a common systematic approach in case management: A possible case is defined as a person presenting with either acute myelitis/paralysis or Guillain-Barré Syndrome (GBS), particularly during periods of EV-D68 circulation. A probable case is defined as a person presenting with symptoms of either acute myelitis/paralysis or GBS and at least one of the following criteria: i) MRI abnormality representing with T2 hyperintensity in spinal cord grey matter with or without hyperintensity at dorsal brain stem, ii) investigations showing an axonal neuropathy including reduced compound motor action potentials with normal conduction velocities and absence of conduction blocks compatible with anterior horn cell disease or iii) detection of enteroviruses in a respiratory specimen obtained from the lower respiratory tract during periods of EV-D68 circulation. A confirmed case is defined as a person presenting with acute flaccid myelitis/paralysis, MRI abnormality and detection of enterovirus-D68-specific nucleic acids in a respiratory specimen using a validated PCR assay targeting the VP1 gene with subsequent sequencing and typing.


Assuntos
Infecções por Enterovirus/diagnóstico , Mielite/virologia , Paralisia/virologia , Enterovirus Humano D , Infecções por Enterovirus/patologia , Humanos , Masculino
4.
FASEB J ; 33(1): 942-952, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30080445

RESUMO

The role for the NOD-like receptor (NLR) P3 inflammasome in enterovirus infection remains controversial. Available data suggest that the NLRP3 inflammasome is protective against enterovirus A71 but detrimental to the host during coxsackievirus B3 (CVB3) infection. CVB3 is a common etiologic agent associated with myocarditis and pancreatitis. Previous findings on the role of NLRP3 in CVB3 were based primarily on indirect evidence. Here, we utilized NLRP3 knockout mice as well as immune and cardiac cells to investigate the direct interplay between CVB3 infection and NLRP3 activation. We demonstrated that NLRP3 knockout mice exhibited more severe disease phenotype after CVB3 infection (significantly higher virus titers), increased myocardial, and pancreatic damage, as well as markedly impaired cardiac function compared to nontransgenic control mice. We further showed that NLRP3 activity was enhanced during early stage of CVB3 infection, as evidenced by increased gene expression and/or secretion of IL-1ß and caspase-1. Finally, we demonstrated that CVB3 inactivates the NLRP3 inflammasome by degrading NLRP3 and its upstream serine/threonine-protein kinase receptor-interacting protein 1/3 via the proteolytic activity of virus-encoded proteinases. Taken together, our results reveal the functional significance of NLRP3 in host antiviral immunity against CVB3 infection and the mechanisms by which CVB3 has evolved to counteract the host defense response.-Wang, C., Fung, G., Deng, H., Jagdeo, J., Mohamud, Y., Xue, Y. C., Jan, E., Hirota, J. A., Luo, H. NLRP3 deficiency exacerbates enterovirus infection in mice.


Assuntos
Infecções por Enterovirus/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Animais , Caspase 1/metabolismo , Linhagem Celular , Infecções por Enterovirus/genética , Infecções por Enterovirus/imunologia , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteólise
5.
J Virol ; 93(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429352

RESUMO

Since the discovery of enterovirus A71 (EV-A71) half a century ago, it has been recognized as the cause of large-scale outbreaks of hand-foot-and-mouth disease worldwide, particularly in the Asia-Pacific region, causing great concern for public health and economic burdens. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rγ-/- (NSG) mice with a human immune system (humanized mice) at the age of 4 weeks were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis, or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection, and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human gamma interferon (IFN-γ), interleukin-8 (IL-8), and IL-17A, was elevated in the EV-A71-infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV-A71 drug candidates in the future.IMPORTANCE Despite causing self-limited hand-food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild-type EV-A71 infection. Our humanized mouse model not only mimics histological symptoms in patients but also allows us to investigate the function of the human immune system during infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV-A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future.


Assuntos
Linfócitos T CD8-Positivos/patologia , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/patologia , Feto/patologia , Carga Viral/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Células Cultivadas , Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Feto/imunologia , Feto/virologia , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
6.
Biomarkers ; 24(3): 277-285, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30521401

RESUMO

Purpose: Hypercatecholaminemia-related heart failure has been proposed as the main cause of enterovirus A71-related (EV-A71) early mortality. The purpose of this study was to measure urine catecholamine concentrations in severe EV-A71-infected children. Methods: A total of 35 children, aged 2.5 ± 2.1 years, were divided into three groups. Group I: 15 septic shock patients, group II: 17 EV-A71-stage-2 patients, and group III: 3 EV-A71-stage-4 patients. The laboratory results, cardiac biomarkers and urine catecholamine concentrations were statistically analysed. Results: Group I had the highest C-reactive protein (CRP) levels and group II had the lowest B-type natriuretic peptide (BNP) and its N-terminal prohormone among the groups (p = 0.039, <0.01 and <0.01, respectively). Group III patients had significantly higher urine catecholamine and troponin-I values among the groups. If urine epinephrine (Epi) >134 ug/gCr, norepinephrine (NE) >176 ug/gCr and vanillylmandelic acid (VMA) >11.7 mg/gCr were used as the cutoff points to differentiate groups II and III, the sensitivities and specificity were all 100%. Conclusions: The significantly elevated urine catecholamine concentrations in EV-A71-stage-4 patients support the hypothesis that hypercatecholaminemia-related heart failure is involved in severe EV-A71 infection. Urine catecholamines could be used as reliable biomarkers for differentiation of severe EV-A71 infection with or without heart failure and septic shock.


Assuntos
Catecolaminas/urina , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/urina , Choque Séptico/urina , Criança , Pré-Escolar , Infecções por Enterovirus/patologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Lactente , Masculino , Choque Séptico/patologia , Choque Séptico/virologia
7.
Virology ; 526: 146-154, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30390563

RESUMO

Enterovirus D68 (EV-D68) is unique among enteroviruses because of the ability to cause severe respiratory disease as well as neurological disease. We developed separate models of respiratory and neurological disease following EV-D68 infection in AG129 mice that respond to antiviral treatment with guanidine. In four-week-old mice infected intranasally, EV-D68 replicates to high titers in lung tissue increasing the proinflammatory cytokines MCP-1 and IL-6. The respiratory infection also produces an acute viremia. In 10-day-old mice infected intraperitoneally, EV-D68 causes a neurological disease with weight-loss, paralysis, and mortality. In our respiratory model, treatment with guanidine provides a two-log reduction in lung virus titers, reduces MCP-1 and IL-6, and prevents histological lesions in the lungs. Importantly, viremia is prevented by early treatment with guanidine. In our neurological model, guanidine treatment protects mice from weight-loss, paralysis, and mortality. These results demonstrate the utility of these models for evaluation of antiviral therapies for EV-D68 infection.


Assuntos
Antivirais/uso terapêutico , Modelos Animais de Doenças , Enterovirus Humano D , Infecções por Enterovirus/tratamento farmacológico , Guanidina/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Animais , Citocinas/metabolismo , Infecções por Enterovirus/patologia , Infecções por Enterovirus/fisiopatologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/virologia , Masculino , Camundongos , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Doenças do Sistema Nervoso/virologia , Infecções Respiratórias/patologia , Infecções Respiratórias/fisiopatologia , Infecções Respiratórias/virologia , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Viremia/prevenção & controle
8.
Pediatr Dev Pathol ; 22(2): 142-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30193561

RESUMO

Massive perivillous fibrin deposition (MFD) is a morphologically defined severe placental lesion associated with perinatal morbidity and mortality. The etiology is unknown, and recurrence risk in subsequent pregnancies is assumed to be high. In most cases, a pathologic immune reaction is supposed to be responsible for the lesion. We report a case of a pregnant woman's suffering from hand, foot, and mouth disease in the 20th gestational week. Subsequently, MFD developed in the placenta and was followed by intrauterine growth restriction and stillbirth in the 29th gestational week. Enterovirus A with high homology to Coxsackievirus A16 was detected in the placenta by means of immunohistochemisty and reverse transcription polymerase chain reaction. This infection could be a rare cause of MFD and should be taken into consideration in the differential diagnosis of the individual etiology. Recurrence risk of virus-related MFD is expected to be lower than in MFD without infectious association.


Assuntos
Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/patologia , Fibrina/metabolismo , Doenças Placentárias/patologia , Natimorto , Biomarcadores/metabolismo , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/metabolismo , Feminino , Humanos , Doenças Placentárias/diagnóstico , Doenças Placentárias/metabolismo , Doenças Placentárias/virologia , Gravidez
9.
Medicine (Baltimore) ; 97(48): e13447, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508963

RESUMO

RATIONALE: Enterovirus 71 (EV71) is identified as the primary cause of hand, foot, and mouth disease (HFMD) and mainly infects the young infants. Though some fatal cases have been reported, the underlying mechanisms of EV71 infection remain elusive and more further pathologic and molecular studies of EV71 infection are needed. PATIENT CONCERNS: A 26-month-old girl with a history of fever and lethargy for 3 days and intermittent seizures for 2 hours associated with rash on 4 limbs was brought to a hospital. DIAGNOSES: The autopsy was performed to identify the cause of death for a medical dispute. The results of histologic examination, immunohistochemistry (IHC), nested reverse transcription polymerase chain reaction (RT-PCR), and viral isolation confirmed that this patient died of EV71 infection. INTERVENTIONS: The patient was transferred to neonatal intensive care unit and was intubated and mechanically ventilated. The other treatment included cardiopulmonary resuscitation and intravenous injection of adrenaline. OUTCOMES: The patient presented persistent coma and intermittent seizures and suddenly developed respiratory arrest and died 16 hours after admission. LESSONS: Our results suggest that EV71 might invade into the central nervous system (CNS) through peripheral nerves which control the digestive tract in the early stage of infection. In addition, we successfully isolated one EV71 strain. Phylogenetic analysis showed that the isolated strain clustered in the C4a of C4 subgenotype. This case also highlights that rapid deterioration in HFMD cases is still a challenge to physicians and they must pay special attention to the infants with HFMD symptoms, particularly in EV71 epidemic areas for early diagnosis and treatment.


Assuntos
Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/virologia , Doença de Mão, Pé e Boca/virologia , Autopsia , Pré-Escolar , China , Enterovirus Humano A/genética , Infecções por Enterovirus/patologia , Evolução Fatal , Feminino , Doença de Mão, Pé e Boca/patologia , Humanos , Filogenia
10.
Nat Commun ; 9(1): 4985, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478256

RESUMO

Coxsackievirus A10 (CVA10), a human type-A Enterovirus (HEV-A), can cause diseases ranging from hand-foot-and-mouth disease to polio-myelitis-like disease. CVA10, together with some other HEV-As, utilizing the molecule KREMEN1 as an entry receptor, constitutes a KREMEN1-dependent subgroup within HEV-As. Currently, there is no vaccine or antiviral therapy available for treating diseases caused by CVA10. The atomic-resolution structure of the CVA10 virion, which is within the KREMEN1-dependent subgroup, shows significant conformational differences in the putative receptor binding sites and serotype-specific epitopes, when compared to the SCARB2-dependent subgroup of HEV-A, such as EV71, highlighting specific differences between the sub-groups. We also report two expanded structures of CVA10, an empty particle and uncoating intermediate at atomic resolution, as well as a medium-resolution genome structure reconstructed using a symmetry-mismatch method. Structural comparisons coupled with previous results, reveal an ordered signal transmission process for enterovirus uncoating, converting exo-genetic receptor-attachment inputs into a generic RNA release mechanism.


Assuntos
Enterovirus/química , Receptores Virais/metabolismo , Desenvelopamento do Vírus , Animais , Capsídeo/metabolismo , Microscopia Crioeletrônica , Enterovirus/ultraestrutura , Infecções por Enterovirus/patologia , Infecções por Enterovirus/virologia , Genoma Viral , Camundongos , Modelos Moleculares
11.
APMIS ; 126(11): 877-882, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30357959

RESUMO

Enterovirus is a common viral infection, which can affect multiple organ systems with an array of clinical presentation such as meningitis, encephalitis, myocarditis, and disseminated infections. The illness is usually asymptomatic and self-limited but few cases can be severe and life-threatening especially when associated with hemophagocytosis. We discuss a fatal case of disseminated enterovirus infection and the histomorphological features of the infection.


Assuntos
Infecções por Enterovirus/virologia , Enterovirus/patogenicidade , Linfo-Histiocitose Hemofagocítica/virologia , Adolescente , Criança , Pré-Escolar , Enterovirus/fisiologia , Infecções por Enterovirus/complicações , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/patologia , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/patologia , Masculino
12.
J Clin Invest ; 128(11): 5163-5177, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30153112

RESUMO

Enterovirus A71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand, foot, and mouth disease and life-threatening encephalitis. We identified an IFN-γ-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pulldown, antibody/antigen blocking, and CRISPR/Cas9-mediated deletion. Hyperexpression and plasma membrane translocation of hWARS were observed in IFN-γ-treated semipermissive (human neuronal NT2) and cDNA-transfected nonpermissive (mouse fibroblast L929) cells, resulting in their sensitization to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to those seen in patients with severe EV-A71 infection. Expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important coxsackievirus A16 (CV-A16) and EV-D68. This is the first report to our knowledge on the discovery of an entry factor, hWARS, that can be induced by IFN-γ for EV-A71 infection. Given that we detected high levels of IFN-γ in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to entry factor expression upon IFN-γ stimulation and the therapeutic options for treating severe EV-A71-associated complications.


Assuntos
Membrana Celular/enzimologia , Enterovirus Humano A/metabolismo , Infecções por Enterovirus/enzimologia , Triptofano-tRNA Ligase/metabolismo , Internalização do Vírus , Animais , Membrana Celular/genética , Modelos Animais de Doenças , Enterovirus Humano A/genética , Infecções por Enterovirus/genética , Infecções por Enterovirus/patologia , Feminino , Humanos , Interferon gama/genética , Camundongos , Camundongos Endogâmicos BALB C , Transdução Genética , Triptofano-tRNA Ligase/genética
13.
JCI Insight ; 3(16)2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30135310

RESUMO

Enterovirus D68 (EV-D68) shares biologic features with rhinovirus (RV). In 2014, a nationwide outbreak of EV-D68 was associated with severe asthma-like symptoms. We sought to develop a mouse model of EV-D68 infection and determine the mechanisms underlying airway disease. BALB/c mice were inoculated intranasally with EV-D68 (2014 isolate), RV-A1B, or sham, alone or in combination with anti-IL-17A or house dust mite (HDM) treatment. Like RV-A1B, lung EV-D68 viral RNA peaked 12 hours after infection. EV-D68 induced airway inflammation, expression of cytokines (TNF-α, IL-6, IL-12b, IL-17A, CXCL1, CXCL2, CXCL10, and CCL2), and airway hyperresponsiveness, which were suppressed by anti-IL-17A antibody. Neutrophilic inflammation and airway responsiveness were significantly higher after EV-D68 compared with RV-A1B infection. Flow cytometry showed increased lineage-, NKp46-, RORγt+ IL-17+ILC3s and γδ T cells in the lungs of EV-D68-treated mice compared with those in RV-treated mice. EV-D68 infection of HDM-exposed mice induced additive or synergistic increases in BAL neutrophils and eosinophils and expression of IL-17, CCL11, IL-5, and Muc5AC. Finally, patients from the 2014 epidemic period with EV-D68 showed significantly higher nasopharyngeal IL-17 mRNA levels compared with patients with RV-A infection. EV-D68 infection induces IL-17-dependent airway inflammation and hyperresponsiveness, which is greater than that generated by RV-A1B, consistent with the clinical picture of severe asthma-like symptoms.


Assuntos
Asma/imunologia , Enterovirus Humano D/imunologia , Infecções por Enterovirus/imunologia , Interleucina-17/metabolismo , Neutrófilos/imunologia , Alérgenos/administração & dosagem , Alérgenos/imunologia , Animais , Asma/patologia , Asma/virologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Modelos Animais de Doenças , Enterovirus/imunologia , Enterovirus/isolamento & purificação , Enterovirus Humano D/isolamento & purificação , Infecções por Enterovirus/patologia , Infecções por Enterovirus/virologia , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Interleucina-17/imunologia , Pulmão/citologia , Pulmão/patologia , Masculino , Camundongos , Nasofaringe/imunologia , Nasofaringe/patologia , Nasofaringe/virologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Pyroglyphidae/imunologia , RNA Mensageiro/metabolismo
14.
Virus Res ; 255: 55-67, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30006004

RESUMO

Stress granules (SGs) are host translationally silent ribonucleo-proteins formed in cells in response to multiple types of environmental stress, including viral infection. We previously showed that the nuclear protein, 68-kDa Src-associated in mitosis protein (Sam68), is recruited to cytoplasm and form the Sam68-positive SGs at 6 hpi, but the Sam68-positive SGs disassembled beyond 12 hpi, suggesting that the SGs might be inhibited during the late stage of Enterovirus 71 (EV71) infection. However, the mechanism and function of this process remains poorly understood. Thus in this study, we demonstrated that EV71 initially induced SGs formation at the early stage of EV71 infection, and confirmed that 2Apro of EV71 was the key viral component that triggered SG formation. In contrast, SGs were diminished as EV71 infection proceeding. At the same time, arsenite-induced SGs were also blocked at the late stage of EV71 infection. This disruption of SGs was caused by viral protease 3Cpro-mediated G3BP1 cleavage. Furthermore, we demonstrated that over-expression of G3BP1-SGs negatively impacted viral replication at the cytopathic effect (CPE), protein, RNA, and viral titer levels. Our novel finding may not only help us to better understand the mechanism how EV71 interacts with the SG response, but also provide mechanistic linkage between cellular stress responses and innate immune activation during EV71 infection.


Assuntos
Cisteína Endopeptidases/metabolismo , Grânulos Citoplasmáticos/metabolismo , DNA Helicases/metabolismo , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/virologia , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Proteínas Virais/metabolismo , Arsenitos/toxicidade , Cisteína Endopeptidases/genética , Citoplasma/metabolismo , Grânulos Citoplasmáticos/enzimologia , Grânulos Citoplasmáticos/virologia , DNA Helicases/genética , Enterovirus Humano A/metabolismo , Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/patologia , Expressão Gênica , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , RNA Helicases/genética , Proteínas com Motivo de Reconhecimento de RNA/genética , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/fisiologia , Proteínas Virais/genética , Replicação Viral
15.
Virus Res ; 255: 117-126, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30030018

RESUMO

Enterovirus 71 (EV71) is one of the major pathogens causing hand, foot, and mouth disease (HFMD) with neurological and systemic complications worldwide, and it is mostly discovered in infants and young children. It is of great significance to establish suitable animal models of EV71 infection on research of distribution and pathogenesis of the virus. In this study, we established a successful infection of a non-mouse-adapted isolate of EV71 via oral route in 7-day-old Mongolian gerbil (Meriones unguiculatus), all of which were paralyzed and died within 10 days post infection. Analysis of virus loads in twelve tissues showed that virus was first detected in intestine, blood, heart, lung, and muscle one day post-infection, and then in the rest of the tissues/organs within the next few days, among which thymus, spleen, spinal cord and muscles had the highest virus titer at 5 days post infection. Pathological examination showed that severe necrosis was observed in skeletal muscle and spinal cord, and edema was observed in both heart and lung. Comparisons of host gene expression of various tissues from infected and non-infected gerbils revealed a general up-regulation of genes related to anti-viral response and a viral receptor gene (sialic acid-linked glycans), as well as a tissue(gut)-specific up-regulation of genes related to neuronal communication. Collectively, our results showed that EV71 could induce severe neurological complications as well as massive tissue damage all over the body, which indicates that oral infection of 7-day gerbils can be a suitable animal model to study the infection of EV71 in human.


Assuntos
Modelos Animais de Doenças , Enterovirus Humano A/fisiologia , Infecções por Enterovirus/virologia , Animais , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/genética , Infecções por Enterovirus/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Gerbillinae , Interações Hospedeiro-Patógeno/genética , Análise de Sobrevida , Carga Viral
16.
J Clin Virol ; 104: 56-60, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29738895

RESUMO

BACKGROUND: Enterovirus (EV) meningitis is the most common form of meningitis. Clinical and biological manifestations may be non-specific, leading to prolonged and costly investigations. OBJECTIVES: To determine the different aspects of EV meningitis and the variables associated with length of stay (LOS) in hospital independently of patients' age. STUDY DESIGN: Single center retrospective study of all EV PCR positive CSF samples during 3.5 years in Bordeaux University Hospital, France. RESULTS: 172 patients were included. 65 were under 3 years old and 49 over 18 years old. 10% of patients had severe forms of the disease. 47 patients (27.3%) had normal CSF count and in 63 patients (36.6%) polynuclear cells predominated in CSF. Procalcitonin, Hoens' score or PCR in stool samples appeared as good markers for enteroviral diagnosis. Time elapsed before PCR results was associated with LOS (p = .002) and should help in limiting investigations in case of aseptic meningitis. CONCLUSION: Rapid availability of EV PCR reduces LOS for patients and contributes to diminish unnecessary procedures and further tests.


Assuntos
Infecções por Enterovirus/patologia , Meningite Viral/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Cefalorraquidiano/virologia , Criança , Pré-Escolar , Enterovirus/isolamento & purificação , Fezes/virologia , Feminino , França , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Pró-Calcitonina/análise , Estudos Retrospectivos , Adulto Jovem
17.
Sci Rep ; 8(1): 6688, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703921

RESUMO

Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD). The current EV71 propagating in Vero (EV-V) or sub-passaged in RD (EV-R) cells was used as a pathogen. Interestingly, EV-R exhibited differential virulence; challenging human scavenger receptor class B2-expressing (hSCARB2-Tg) mice with EV71 revealed that EV-V was more virulent than EV-R: 100% of mice that received lethal amounts of EV-V died, while all the mice that received EV-R survived. Severe pathogenesis correlated with viral burdens and proinflammatory cytokine levels were observed in EV-V-challenged mice, but controversy in EV-R-challenged mice. Consensus sequence analysis revealed EV-R rapidly acquired complete mutations at E145G and S241L and partial mutations at V146I of VP1, and acquired a T to C substitution at nucleotide 494 of the 5'-UTR. EV-R exhibited higher binding affinity for another EV71 receptor, human P-selectin glycoprotein ligand-1 (hPSGL-1), than EV-V. Both EV71s exhibited no significant difference in binding to hSCARB2. The molecular modelling indicate that these mutations might influence EV71 engagement with PSGL-1 and in vivo virulence.


Assuntos
Regiões 5' não Traduzidas , Enterovirus Humano A/crescimento & desenvolvimento , Enterovirus Humano A/patogenicidade , Infecções por Enterovirus/patologia , Glicoproteínas de Membrana/metabolismo , Mutação , Proteínas Estruturais Virais/genética , Animais , Linhagem Celular , Citocinas/sangue , Análise Mutacional de DNA , Modelos Animais de Doenças , Infecções por Enterovirus/virologia , Humanos , Camundongos , Receptores Virais/metabolismo , Análise de Sobrevida , Carga Viral , Proteínas Virais , Proteínas Estruturais Virais/metabolismo , Virulência , Ligação Viral
19.
Epidemiol Infect ; 146(6): 788-798, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29526169

RESUMO

Enterovirus A-71 (EV-A71) may be fatal, but the natural history, symptoms, and signs are poorly understood. This study aimed to examine the natural history of fatal EV-A71 infection and to identify the symptoms and signs of early warning of deterioration. This was a clinical observational study of fatal cases of EV-A71 infection treated at five Chinese hospitals between 1 January 2010 and 31 December 2012. We recorded and analysed 91 manifestations of EV-A71 infection in order to identify early prognosis indicators. There were 54 fatal cases. Median age was 21.5 months (Q1-Q3: 12-36). The median duration from onset to death was 78.5 h (range, 6 to 432). The multilayer perceptron analysis showed that ataxia respiratory, ultrahyperpyrexia, excessive tachycardia, refractory shock, absent pharyngeal reflex, irregular respiratory rhythm, hyperventilation, deep coma, pulmonary oedema and/or haemorrhage, excessive hypertension, tachycardia, somnolence, CRT extension, fatigue or sleepiness and age were associated with death. Autopsy findings (n = 2) showed neuronal necrosis, softening, perivascular cuffing, colloid and neuronophagia phenomenon in the brainstem. The fatal cases of enterovirus A71 had neurologic involvement, even at the early stage. Direct virus invasion through the neural pathway and subsequent brainstem damage might explain the rapid progression to death.


Assuntos
Infecções do Sistema Nervoso Central/mortalidade , Infecções do Sistema Nervoso Central/patologia , Enterovirus Humano A/isolamento & purificação , Infecções por Enterovirus/mortalidade , Infecções por Enterovirus/patologia , Adolescente , Infecções do Sistema Nervoso Central/epidemiologia , Criança , Pré-Escolar , China/epidemiologia , Progressão da Doença , Infecções por Enterovirus/epidemiologia , Feminino , Humanos , Lactente , Masculino , Prognóstico , Fatores de Tempo
20.
Cell Rep ; 22(12): 3292-3303, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29562184

RESUMO

Picornaviruses have evolved to hijack host cellular machinery, including the autophagic pathway. However, the mechanisms remain largely unclear. We use coxsackievirus B3 (CVB3) as a model organism to explore the possible role of picornavirus subversion of the autophagic pathway in viral infection. Our in vivo and in vitro experiments demonstrate that CVB3 infection causes a significant, albeit incomplete, inhibition of autophagic flux by limiting the fusion of autophagosomes with lysosomes and/or late endosomes. Furthermore, we show that CVB3 specifically targets SNARE protein SNAP29 and adaptor protein PLEKHM1, two critical proteins known to regulate autophagosome fusion, for cleavage through the catalytic activity of viral proteinase 3C, ultimately impairing the formation of SNARE complexes. Finally, we demonstrate that loss of SNAP29/PLEKHM1 inhibits autophagic flux, resulting in increased viral replication. Collectively, our study reveals a mechanism that supports an emerging model whereby CVB3 hijacks the autophagic machinery to facilitate its own propagation.


Assuntos
Infecções por Enterovirus/metabolismo , Infecções por Enterovirus/virologia , Enterovirus/fisiologia , Proteínas SNARE/metabolismo , Replicação Viral , Animais , Autofagia/efeitos dos fármacos , Enterovirus/genética , Infecções por Enterovirus/patologia , Células HeLa , Humanos , Macrolídeos/farmacologia , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo
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