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2.
PLoS Pathog ; 15(2): e1007564, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30817809

RESUMO

There are a number of vaccine candidates under development against a small number of the most common outbreak filoviruses all employing the virus glycoprotein (GP) as the vaccine immunogen. However, antibodies induced by such GP vaccines are typically autologous and limited to the other members of the same species. In contrast, T-cell vaccines offer a possibility to design a single pan-filovirus vaccine protecting against all known and even likely existing, but as yet unencountered members of the family. Here, we used a cross-filovirus immunogen based on conserved regions of the filovirus nucleoprotein, matrix and polymerase to construct simian adenovirus- and poxvirus MVA-vectored vaccines, and in a proof-of-concept study demonstrated a protection of the BALB/c and C57BL/6J mice against high, lethal challenges with Ebola and Marburg viruses, two distant members of the family, by vaccine-elicited T cells in the absence of GP antibodies.


Assuntos
Filoviridae/imunologia , Linfócitos T/imunologia , Vacinas Virais/farmacologia , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Vacinas contra Ebola , Ebolavirus/patogenicidade , Feminino , Filoviridae/metabolismo , Filoviridae/patogenicidade , Doença pelo Vírus Ebola , Imunidade Celular/imunologia , Masculino , Marburgvirus/patogenicidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estudo de Prova de Conceito , Linfócitos T/metabolismo
3.
PLoS Negl Trop Dis ; 13(3): e0007209, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30845141

RESUMO

BACKGROUND: In the wake of the West African Ebola virus disease (EVD) outbreak of 2014-2016, thousands of EVD survivors began to manifest a constellation of systemic and ophthalmic sequelae. Besides systemic arthralgias, myalgias, and abdominal pain, patients were developing uveitis, a spectrum of inflammatory eye disease leading to eye pain, redness, and vision loss. To investigate this emerging eye disease, resources and equipment were needed to promptly evaluate this sight-threatening condition, particularly given our identification of Ebola virus in the ocular fluid of an EVD survivor during disease convalescence. METHODOLOGY/PRINCIPAL FINDINGS: A collaborative effort involving ophthalmologists, infectious disease specialists, eye care nurses, and physician leadership at Eternal Love Winning Africa (ELWA) Hospital in Liberia led to the development of a unique screening eye clinic for EVD survivors to screen, treat, and refer patients for more definitive care. Medications, resources, and equipment were procured from a variety of sources including discount websites, donations, purchasing with humanitarian discounts, and limited retail to develop a screening eye clinic and rapidly perform detailed ophthalmologic exams. Findings were documented in 96 EVD survivors to inform public health officials and eye care providers of the emerging disease process. Personal protective equipment was tailored to the environment and implications of EBOV persistence within intraocular fluid. CONCLUSIONS/SIGNIFICANCE: A screening eye clinic was feasible and effective for the rapid screening, care, and referral of EVD survivors with uveitis and retinal disease. Patients were screened promptly for an initial assessment of the disease process, which has informed other efforts within West Africa related to immediate patient care needs and our collective understanding of EVD sequelae. Further attention is needed to understand the pathogensis and treatment of ophthalmic sequelae given recent EVD outbreaks in West Africa and ongoing outbreak within Democratic Republic of Congo.


Assuntos
Instituições de Assistência Ambulatorial , Programas de Triagem Diagnóstica , Implementação de Plano de Saúde , Doença pelo Vírus Ebola/complicações , Transtornos da Visão/diagnóstico , Transtornos da Visão/virologia , Programas de Triagem Diagnóstica/economia , Programas de Triagem Diagnóstica/estatística & dados numéricos , Surtos de Doenças , Ebolavirus/patogenicidade , Economia Hospitalar , Equipamentos e Provisões Hospitalares/economia , Olho/virologia , Recursos em Saúde , Hospitais , Humanos , Libéria , Sobreviventes , Uveíte/diagnóstico , Uveíte/etiologia
4.
Proc Natl Acad Sci U S A ; 116(9): 3919-3928, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808769

RESUMO

Ebola virus disease (EVD) often leads to severe and fatal outcomes in humans with early supportive care increasing the chances of survival. Profiling the human plasma lipidome provides insight into critical illness as well as diseased states, as lipids have essential roles as membrane structural components, signaling molecules, and energy sources. Here we show that the plasma lipidomes of EVD survivors and fatalities from Sierra Leone, infected during the 2014-2016 Ebola virus outbreak, were profoundly altered. Focusing on how lipids are associated in human plasma, while factoring in the state of critical illness, we found that lipidome changes were related to EVD outcome and could identify states of disease and recovery. Specific changes in the lipidome suggested contributions from extracellular vesicles, viremia, liver dysfunction, apoptosis, autophagy, and general critical illness, and we identified possible targets for therapies enhancing EVD survival.


Assuntos
Estado Terminal/epidemiologia , Doença pelo Vírus Ebola/genética , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Adolescente , Adulto , Criança , Surtos de Doenças , Ebolavirus/genética , Ebolavirus/patogenicidade , Feminino , Regulação da Expressão Gênica/genética , Doença pelo Vírus Ebola/sangue , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/virologia , Humanos , Lipídeos/sangue , Masculino , Serra Leoa/epidemiologia , Adulto Jovem
5.
Health Secur ; 17(1): 35-45, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30779607

RESUMO

The 2013-2016 epidemic of Ebola virus disease (EVD) that originated in West Africa underscored many of the challenges to conducting clinical research during an ongoing infectious disease epidemic, both in the most affected countries of Guinea, Liberia, and Sierra Leone, as well as in the United States and Europe, where a total of 27 patients with EVD received care in biocontainment units. The Special Pathogens Research Network (SPRN) was established in the United States in November 2016 to provide an organizational structure to leverage the expertise of the 10 Regional Ebola and Other Special Pathogen Treatment Centers (RESPTCs); it was intended to develop and support infrastructure to improve readiness to conduct clinical research in the United States. The network enables the rapid activation and coordination of clinical research in the event of an epidemic and facilitates opportunities for multicenter research when the RESPTCs are actively caring for patients requiring a biocontainment unit. Here we provide an overview of opportunities identified in the clinical research infrastructure during the West Africa EVD epidemic and the SPRN activities to meet the ongoing challenges in the context of Ebola virus and other special pathogens.


Assuntos
Pesquisa Biomédica/métodos , Ebolavirus/patogenicidade , Serviços Médicos de Emergência/organização & administração , Controle de Infecções/métodos , Contramedidas Médicas , África/epidemiologia , Contenção de Riscos Biológicos/métodos , Epidemias/prevenção & controle , Europa (Continente) , Doença pelo Vírus Ebola/epidemiologia , Humanos , Centros de Atenção Terciária , Estados Unidos
6.
Nat Commun ; 10(1): 285, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655525

RESUMO

There are no approved therapies for Ebola virus infection. Here, to find potential therapeutic targets, we perform a screen for genes essential for Ebola virus (EBOV) infection. We identify GNPTAB, which encodes the α and ß subunits of N-acetylglucosamine-1-phosphate transferase. We show that EBOV infection of a GNPTAB knockout cell line is impaired, and that this is reversed by reconstituting GNPTAB expression. Fibroblasts from patients with mucolipidosis II, a disorder associated with mutations in GNPTAB, are refractory to EBOV, whereas cells from their healthy parents support infection. Impaired infection correlates with loss of the expression of cathepsin B, known to be essential for EBOV entry. GNPTAB activity is dependent upon proteolytic cleavage by the SKI-1/S1P protease. Inhibiting this protease with the small-molecule PF-429242 blocks EBOV entry and infection. Disruption of GNPTAB function may represent a strategy for a host-targeted therapy for EBOV.


Assuntos
Antivirais/farmacologia , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/tratamento farmacológico , Mucolipidoses/patologia , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Internalização do Vírus/efeitos dos fármacos , Células A549 , Animais , Antivirais/uso terapêutico , Catepsina B/metabolismo , Cercopithecus aethiops , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Fibroblastos , Técnicas de Inativação de Genes , Doença pelo Vírus Ebola/virologia , Humanos , Mucolipidoses/genética , Pró-Proteína Convertases/antagonistas & inibidores , Pró-Proteína Convertases/metabolismo , Inibidores de Proteases/farmacologia , Pirrolidinas/farmacologia , Serina Endopeptidases/metabolismo , Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores , Células Vero , Sequenciamento Completo do Genoma
7.
Cell Host Microbe ; 25(1): 39-48.e5, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629917

RESUMO

Passive administration of monoclonal antibodies (mAbs) is a promising therapeutic approach for Ebola virus disease (EVD). However, all mAbs and mAb cocktails that have entered clinical development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against outbreak-causing Bundibugyo virus (BDBV) and Sudan virus (SUDV). Here, we advance MBP134, a cocktail of two broadly neutralizing human mAbs, ADI-15878 from an EVD survivor and ADI-23774 from the same survivor but specificity-matured for SUDV GP binding affinity, as a candidate pan-ebolavirus therapeutic. MBP134 potently neutralized all ebolaviruses and demonstrated greater protective efficacy than ADI-15878 alone in EBOV-challenged guinea pigs. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional improvement relative to its precursor in protective efficacy against EBOV and SUDV in guinea pigs. MBP134AF is an optimized mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Bem-Estar do Animal , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/uso terapêutico , Antivirais , Modelos Animais de Doenças , Ebolavirus/patogenicidade , Epitopos/imunologia , Feminino , Filoviridae/imunologia , Cobaias , Doença pelo Vírus Ebola/virologia , Humanos , Imunoterapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Recombinantes/imunologia , Resultado do Tratamento
8.
Cell Host Microbe ; 25(1): 49-58.e5, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30629918

RESUMO

Recent and ongoing outbreaks of Ebola virus disease (EVD) underscore the unpredictable nature of ebolavirus reemergence and the urgent need for antiviral treatments. Unfortunately, available experimental vaccines and immunotherapeutics are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against other ebolaviruses associated with EVD, including Sudan virus (SUDV) and Bundibugyo virus (BDBV). Here we show that MBP134AF, a pan-ebolavirus therapeutic comprising two broadly neutralizing human antibodies (bNAbs), affords unprecedented effectiveness and potency as a therapeutic countermeasure to antigenically diverse ebolaviruses. MBP134AF could fully protect ferrets against lethal EBOV, SUDV, and BDBV infection, and a single 25-mg/kg dose was sufficient to protect NHPs against all three viruses. The development of MBP134AF provides a successful model for the rapid discovery and translational advancement of immunotherapeutics targeting emerging infectious diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Ebolavirus/patogenicidade , Furões/virologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Bem-Estar do Animal , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/isolamento & purificação , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/administração & dosagem , Linhagem Celular , Cercopithecus aethiops , Modelos Animais de Doenças , Feminino , Filoviridae/imunologia , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/prevenção & controle , Infecções por Filoviridae/virologia , Glicoproteínas/imunologia , Cobaias , Células HEK293 , Doença pelo Vírus Ebola/virologia , Humanos , Células Matadoras Naturais , Macaca , Macaca fascicularis , Masculino , Primatas , Análise de Sobrevida , Resultado do Tratamento , Proteínas Virais/imunologia
9.
Viruses ; 10(8)2018 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-30126221

RESUMO

After more than 28,000 Ebola virus disease cases and at least 11,000 deaths in West Africa during the 2014⁻2016 epidemic, the world remains without a licensed vaccine or therapeutic broadly available and demonstrated to alleviate suffering. This deficiency has been felt acutely in the two, short, following years with two Ebola virus outbreaks in the Democratic Republic of Congo (DRC), and a Marburg virus outbreak in Uganda. Despite billions of U.S. dollars invested in developing medical countermeasures for filoviruses in the antecedent decades, resulting in an array of preventative, diagnostic, and therapeutic products, none are available on commercial shelves. This paper explores why just-in-time research efforts in the field during the West Africa epidemic failed, as well as some recent initiatives to prevent similarly lost opportunities.


Assuntos
Pesquisa Biomédica/organização & administração , Surtos de Doenças , Medicina de Emergência/organização & administração , Doença pelo Vírus Ebola/epidemiologia , Doença do Vírus de Marburg/epidemiologia , Animais , República Democrática do Congo/epidemiologia , Ebolavirus/patogenicidade , Ebolavirus/fisiologia , Saúde Global , Doença pelo Vírus Ebola/mortalidade , Doença pelo Vírus Ebola/prevenção & controle , Doença pelo Vírus Ebola/virologia , Humanos , Doença do Vírus de Marburg/mortalidade , Doença do Vírus de Marburg/prevenção & controle , Doença do Vírus de Marburg/virologia , Marburgvirus/patogenicidade , Marburgvirus/fisiologia , Análise de Sobrevida , Uganda/epidemiologia
10.
Sensors (Basel) ; 18(6)2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29789514

RESUMO

Optical biosensors based on scattered-light measurements are being developed for rapid and label-free detection of single virions captured from body fluids. Highly controlled, stable, and non-biohazardous reference materials producing virus-like signals are valuable tools to calibrate, evaluate, and refine the performance of these new optical biosensing methods. To date, spherical polymer nanoparticles have been the only non-biological reference materials employed with scattered-light biosensing techniques. However, pathogens like filoviruses, including the Ebola virus, are far from spherical and their shape strongly affects scattered-light signals. Using electron beam lithography, we fabricated nanostructures resembling individual filamentous virions attached to a biosensing substrate (silicon wafer overlaid with silicon oxide film) and characterized their dimensions with scanning electron and atomic force microscopes. To assess the relevance of these nanostructures, we compared their signals across the visible spectrum to signals recorded from Ebola virus-like particles which exhibit characteristic filamentous morphology. We demonstrate the highly stable nature of our nanostructures and use them to obtain new insights into the relationship between virion dimensions and scattered-light signal.


Assuntos
Técnicas Biossensoriais , Ebolavirus/isolamento & purificação , Nanoestruturas/química , Líquidos Corporais/virologia , Ebolavirus/patogenicidade , Elétrons , Filoviridae/isolamento & purificação , Filoviridae/patogenicidade , Doença pelo Vírus Ebola/diagnóstico , Doença pelo Vírus Ebola/virologia , Humanos , Microscopia de Força Atômica , Nanotecnologia/métodos , Polímeros/química
11.
Sci Rep ; 8(1): 864, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29339750

RESUMO

Ebola virus (EBOV), isolate Makona, was the causative agent of the West African epidemic devastating predominantly Guinea, Liberia and Sierra Leone from 2013-2016. While several experimental vaccine and treatment approaches have been accelerated through human clinical trials, there is still no approved countermeasure available against this disease. Here, we report the construction and preclinical efficacy testing of a novel recombinant modified vaccinia Ankara (MVA)-based vaccine expressing the EBOV-Makona glycoprotein GP and matrix protein VP40 (MVA-EBOV). GP and VP40 form EBOV-like particles and elicit protective immune responses. In this study, we report 100% protection against lethal EBOV infection in guinea pigs after prime/boost vaccination with MVA-EBOV. Furthermore, this MVA-EBOV protected macaques from lethal disease after a single dose or prime/boost vaccination. The vaccine elicited a variety of antibody responses to both antigens, including neutralizing antibodies and antibodies with antibody-dependent cellular cytotoxic activity specific for GP. This is the first report that a replication-deficient MVA vector can confer full protection against lethal EBOV challenge after a single dose vaccination in macaques.


Assuntos
Ebolavirus/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vaccinia/genética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Ebolavirus/genética , Ebolavirus/patogenicidade , Feminino , Cobaias , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/mortalidade , Doença pelo Vírus Ebola/prevenção & controle , Doença pelo Vírus Ebola/veterinária , Macaca , Masculino , Nucleoproteínas/genética , Taxa de Sobrevida , Vacinação , Proteínas do Core Viral/genética , Carga Viral
13.
Vaccine ; 36(36): 5454-5459, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-28780120

RESUMO

We have just witnessed the largest and most devastating outbreak of Ebola virus disease, which highlighted the urgent need for development of an efficacious vaccine that could be used to curtail future outbreaks. Prior to 2014, there had been limited impetus worldwide to develop a vaccine since the virus was first discovered in 1976. Though too many lives were lost during this outbreak, it resulted in the significantly accelerated clinical development of a number of candidate vaccines through an extraordinary collaborative global effort coordinated by the World Health Organisation (WHO) and involving a number of companies, trial centres, funders, global stakeholders and agencies. We have acquired substantial safety and immunogenicity data on a number of vaccines in Caucasian and African populations. The rapid pace of events led to the initiation of the landmark efficacy trial testing the rVSV-vectored vaccine, which showed high level efficacy in an outbreak setting when deployed using an innovative ring vaccination strategy. Though the Public Health Emergency of International Concern (PHEIC) declared by the WHO has now been lifted, the global scientific community faces numerous challenges ahead to ensure that there is a licensed, deployable vaccine available for use in future outbreaks for at least the Zaire and Sudan strains of Ebola virus. There remain several unanswered questions on the durability of protection, mechanistic immunological correlates and preferred deployment strategies. This review outlines a brief history of the development of Ebola vaccines, the significant progress made since the scale of the outbreak became apparent, some lessons learnt and how they could shape future development of vaccines and the management of similar outbreaks.


Assuntos
Vacinas contra Ebola/uso terapêutico , Ebolavirus/imunologia , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/prevenção & controle , África Ocidental , Humanos , Organização Mundial da Saúde
14.
Rev. esp. salud pública ; 92: 0-0, 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-177599

RESUMO

Fundamentos: El Ébola es una enfermedad grave y mortal, su contagio es rápido entre personas. El seguimiento y vigilancia de los contactos es una medida efectiva para frenar una epidemia. El objetivo de este trabajo fue analizar la efectividad de una intervención basada en la detección de nuevos casos de Ébola y el seguimiento de personas en cuarentena. Métodos: Estudio analítico longitudinal con intervención comunitaria. Se instauró una vigilancia continua a la población de Lunsar (Sierra Leona) para detectar nuevos casos de Ébola, estableciendo una cuarentena con seguimiento y control a 96 personas. Durante el proceso, se realizaron actividades de Promoción de la Salud. El periodo de estudio comprende desde el 9 de Febrero al 24 de Marzo de 2015. Los datos obtenidos se analizaron con el paquete estadistico SPSS versión 20.0. Resultados: 7 casas, con 96 personas, fueron puestas en cuarentena con una media de 24,2±4,9 días. Al finalizar el seguimiento, 16 (16,7%) personas fueron positivas al Ébola, falleciendo 13 (81,2%) de ellas. El odds de prevalencia de riesgo de contagio es mayor en personas tras haber realizado prácticas funerarias en casa (OR=3,64, p<0,001). En las personas, no contagiadas durante la cuarentena, la odds ratio asociada a la supervivencia se multiplica por 21 veces (OR=21, p<0,001). Conclusiones: Los contagios se han producido en las familias donde ha habido un fallecido en casa. Las tareas realizadas por el equipo socio-sanitario han podido influir, dado que solamente se contagiaron el 16,7% de las personas en cuarentena. Las enfermeras resultaron imprescindibles a través de la educación sanitaria y el apoyo social a las familias


Background: Ebola Virus Disease (EVD) is a severe and, often fatal illness. Ebola spread is fast among human beings. Monitoring and surveillance of contacts is an effective measure to stop an epidemic. The aim of this research is to analyze the effectiveness of an intervention based on contact tracing and monitoring the quarantine people. Methods: Longitudinal analytical study with community intervention. The intervention consisted of establishing a continuous surveillance of the population of Lunsar (Sierra Leone) to detect new cases of Ebola, establishing quarantine to 96 people. During the process, Health Promotion activities were carried out. The study period includes from February 9 to March 24, 2015. The data obtained were analyzed with the statistical package SPSS, version 20.0. Results: 7 houses, with 96 people in total, were quarantined (the average quarantine was 24.2 ± 4.9 days). At the end of the follow-up, 16 (16.7%) people tested positive for Ebola, 13 (81.2%) of whom ended up dying. The Ebola risk of infection was higher after having performed funeral practices at home (OR = 3.64, p <0.001). Furthermore, the odds ratio associated with survival result 21 times greater (OR = 21, p <0.001) in people not infected during quarantine. Conclusions: The contagions have occurred in families where there has been a deceaded at home. The tasks performed by the outreach team have been able to influence that only 16.7% of the quarantine people were infected. Nurses were essential in health promotion and social support to families


Assuntos
Humanos , Doença pelo Vírus Ebola/epidemiologia , Ebolavirus/patogenicidade , Quarentena/métodos , Cuidados de Enfermagem/métodos , Surtos de Doenças , Doença pelo Vírus Ebola/transmissão , Busca de Comunicante , Apoio Social , Educação em Saúde/métodos , Avaliação de Eficácia-Efetividade de Intervenções
15.
Artigo em Inglês | MEDLINE | ID: mdl-29209594

RESUMO

Understanding how infected cells respond to Ebola virus (EBOV) and how this response changes during the process of viral replication and transcription are very important for establishing effective antiviral strategies. In this study, we conducted a genome-wide screen to identify long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and mRNAs differentially expressed during replication and transcription using a tetracistronic transcription and replication-competent virus-like particle (trVLP) system that models the life cycle of EBOV in 293T cells. To characterize the expression patterns of these differentially expressed RNAs, we performed a series cluster analysis, and up- or down-regulated genes were selected to establish a gene co-expression network. Competing endogenous RNA (ceRNA) networks based on the RNAs responsible for the effects induced by EBOV replication and transcription in human cells, including circRNAs, lncRNAs, miRNAs, and mRNAs, were constructed for the first time. Based on these networks, the interaction details of circRNA-chr19 were explored. Our results demonstrated that circRNA-chr19 targeting miR-30b-3p regulated CLDN18 expression by functioning as a ceRNA. These findings may have important implications for further studies of the mechanisms of EBOV replication and transcription. These RNAs potentially have important functions and may be promising targets for EBOV therapy.


Assuntos
Ebolavirus/fisiologia , Perfilação da Expressão Gênica , Doença pelo Vírus Ebola/genética , Interações Hospedeiro-Patógeno/genética , RNA/genética , RNA/metabolismo , Replicação Viral/fisiologia , Ebolavirus/patogenicidade , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Doença pelo Vírus Ebola/metabolismo , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno/fisiologia , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA
17.
Emerg Infect Dis ; 23(12): 2081-2084, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29148368

RESUMO

In December 2014, Ebola virus disease (EVD) was diagnosed in a healthcare worker in the United Kingdom after the worker returned from an Ebola treatment center in Sierra Leone. The worker flew on 2 flights during the early stages of disease. Follow-up of 238 contacts showed no evidence of secondary transmission of Ebola virus.


Assuntos
Busca de Comunicante , Surtos de Doenças , Ebolavirus/patogenicidade , Pessoal de Saúde , Doença pelo Vírus Ebola/virologia , Adulto , Aeronaves , Ebolavirus/fisiologia , Feminino , Doença pelo Vírus Ebola/terapia , Doença pelo Vírus Ebola/transmissão , Humanos , Cooperação Internacional , Serra Leoa/epidemiologia , Viagem , Reino Unido/epidemiologia
18.
Viruses ; 9(11)2017 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-29109373

RESUMO

Ebola virus (EBOV) is a filovirus that can cause Ebola virus disease (EVD). No approved vaccines or therapies exist for filovirus infections, despite an urgent need. The development and testing of effective countermeasures against EBOV requires use of animal models and a thorough understanding of how the model aligns with EVD in humans. The majority of published studies report outcomes of parenteral exposures for emulating needle stick transmission. However, based on data from EVD outbreaks, close contact exposures to infected bodily fluid seems to be one of the primary routes of EBOV transmission. Thus, further work is needed to develop models that represent mucosal exposure. To characterize the outcome of mucosal exposure to EBOV, cynomolgus macaques were exposed to EBOV via intranasal (IN) route using the LMA® mucosal atomization device (LMA® MAD). For comparison, four non-human primates (NHPs) were exposed to EBOV via intramuscular (IM) route. This IN exposure model was uniformly lethal and correlated with a statistically significant delay in time to death when compared to exposure via the IM route. This more closely reflects the timeframes observed in human infections. An IN model of exposure offers an attractive alternative to other models as it can offer insight into the consequences of exposure via a mucosal surface and allows for screening countermeasures via a different exposure route.


Assuntos
Modelos Animais de Doenças , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/virologia , Administração Intranasal , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Ebolavirus/imunologia , Ebolavirus/isolamento & purificação , Doença pelo Vírus Ebola/imunologia , Humanos , Macaca fascicularis
19.
BMC Infect Dis ; 17(1): 597, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28854896

RESUMO

BACKGROUND: During the 2013-2016 West Africa Ebola virus disease (EVD) epidemic, some EVD patients, mostly health care workers, were evacuated to Europe and the USA. CASE PRESENTATION: In May 2015, a 37-year old male nurse contracted Ebola virus disease in Sierra Leone. After Ebola virus detection in plasma, he was medically-evacuated to Italy. At admission, rhabdomyolysis was clinically and laboratory-diagnosed and was treated with aggressive hydration, oral favipiravir and intravenous investigational monoclonal antibodies against Ebola virus. The recovery clinical phase was complicated by a febrile thrombocytopenic syndrome with pericardial effusion treated with corticosteroids for 10 days and indomethacin for 2 months. No evidence of recurrence is reported. CONCLUSIONS: A febrile thrombocytopenic syndrome with pericardial effusion during the recovery phase of EVD appears to be uncommon. Clinical improvement with corticosteroid treatment suggests that an immune-mediated mechanism contributed to the pericardial effusion.


Assuntos
Doença pelo Vírus Ebola/complicações , Derrame Pericárdico/tratamento farmacológico , Derrame Pericárdico/etiologia , Rabdomiólise/tratamento farmacológico , Rabdomiólise/etiologia , Corticosteroides/uso terapêutico , Adulto , Amidas/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Ebolavirus/imunologia , Ebolavirus/patogenicidade , Pessoal de Saúde , Doença pelo Vírus Ebola/tratamento farmacológico , Humanos , Indometacina/uso terapêutico , Itália , Masculino , Derrame Pericárdico/virologia , Pirazinas/uso terapêutico , Rabdomiólise/virologia , Serra Leoa
20.
J Virol ; 91(23)2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28931675

RESUMO

Ebolavirus and Marburgvirus comprise two genera of negative-sense single-stranded RNA viruses that cause severe hemorrhagic fevers in humans. Despite considerable research efforts, the molecular events following Ebola virus (EBOV) infection are poorly understood. With the view of identifying host factors that underpin EBOV pathogenesis, we compared the transcriptomes of EBOV-infected human, pig, and bat kidney cells using a transcriptome sequencing (RNA-seq) approach. Despite a significant difference in viral transcription/replication between the cell lines, all cells responded to EBOV infection through a robust induction of extracellular growth factors. Furthermore, a significant upregulation of activator protein 1 (AP1) transcription factor complex members FOS and JUN was observed in permissive cell lines. Functional studies focusing on human cells showed that EBOV infection induces protein expression, phosphorylation, and nuclear accumulation of JUN and, to a lesser degree, FOS. Using a luciferase-based reporter, we show that EBOV infection induces AP1 transactivation activity within human cells at 48 and 72 h postinfection. Finally, we show that JUN knockdown decreases the expression of EBOV-induced host gene expression. Taken together, our study highlights the role of AP1 in promoting the host gene expression profile that defines EBOV pathogenesis.IMPORTANCE Many questions remain about the molecular events that underpin filovirus pathophysiology. The rational design of new intervention strategies, such as postexposure therapeutics, will be significantly enhanced through an in-depth understanding of these molecular events. We believe that new insights into the molecular pathogenesis of EBOV may be possible by examining the transcriptomic response of taxonomically diverse cell lines (derived from human, pig, and bat). We first identified the responsive pathways using an RNA-seq-based transcriptomics approach. Further functional and computational analysis focusing on human cells highlighted an important role for the AP1 transcription factor in mediating the transcriptional response to EBOV infection. Our study sheds new light on how host transcription factors respond to and promote the transcriptional landscape that follows viral infection.


Assuntos
Perfilação da Expressão Gênica , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno , Fator de Transcrição AP-1/metabolismo , Animais , Linhagem Celular , Quirópteros , Ebolavirus/patogenicidade , Genes fos , Genes jun , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Rim/citologia , Rim/virologia , Fosforilação , Suínos , Fator de Transcrição AP-1/genética , Proteínas Virais , Replicação Viral
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