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1.
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
2.
Nat Commun ; 10(1): 105, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30631063

RESUMO

The 2013-2016 Ebola virus (EBOV) disease epidemic demonstrated the grave consequences of filovirus epidemics in the absence of effective therapeutics. Besides EBOV, two additional ebolaviruses, Sudan (SUDV) and Bundibugyo (BDBV) viruses, as well as multiple variants of Marburg virus (MARV), have also caused high fatality epidemics. Current experimental EBOV monoclonal antibodies (mAbs) are ineffective against SUDV, BDBV, or MARV. Here, we report that a cocktail of two broadly neutralizing ebolavirus mAbs, FVM04 and CA45, protects nonhuman primates (NHPs) against EBOV and SUDV infection when delivered four days post infection. This cocktail when supplemented by the anti-MARV mAb MR191 exhibited 100% efficacy in MARV-infected NHPs. These findings provide a solid foundation for clinical development of broadly protective immunotherapeutics for use in future filovirus epidemics.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Ebolavirus/imunologia , Infecções por Filoviridae/imunologia , Marburgvirus/imunologia , Doenças dos Primatas/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Ebolavirus/classificação , Ebolavirus/efeitos dos fármacos , Ebolavirus/fisiologia , Infecções por Filoviridae/terapia , Infecções por Filoviridae/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Imunoterapia/métodos , Marburgvirus/efeitos dos fármacos , Marburgvirus/fisiologia , Doenças dos Primatas/terapia , Doenças dos Primatas/virologia , Primatas , Resultado do Tratamento
4.
Zool Res ; 39(1): 15-24, 2018 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-29511141

RESUMO

The family Filoviridae, which includes the genera Marburgvirus and Ebolavirus, contains some of the most pathogenic viruses in humans and non-human primates (NHPs), causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research.


Assuntos
Infecções por Filoviridae , Animais , Cricetinae , Modelos Animais de Doenças , Furões , Infecções por Filoviridae/etiologia , Infecções por Filoviridae/terapia , Infecções por Filoviridae/virologia , Cobaias , Doença pelo Vírus Ebola/etiologia , Doença pelo Vírus Ebola/terapia , Doença pelo Vírus Ebola/virologia , Doença do Vírus de Marburg/etiologia , Doença do Vírus de Marburg/terapia , Doença do Vírus de Marburg/virologia , Mesocricetus , Camundongos , Primatas
5.
Methods Mol Biol ; 1628: 133-142, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28573616

RESUMO

Innate immunity is the first line of defense against virus infections and is marked by production of type I interferons (IFN), a family of cytokines that includes IFN-ß and several IFN-αs. For the filoviruses and many other RNA viruses that replicate in the cytoplasm, the RIG-I-like pattern recognition receptors (RLRs) are potential triggers of IFN production. To counteract such innate antiviral responses, many viruses encode proteins that antagonize RLR signaling. Ebola virus (EBOV) and other filoviruses produce VP35 proteins that block IFN induction via RLR signaling. We describe here cell-based reporter gene assays that quantify the IFN-antagonist function of filovirus VP35 proteins by assessing activation of the IFN-ß promoter.


Assuntos
Infecções por Filoviridae/genética , Filoviridae/genética , Interferon Tipo I/genética , Proteínas Virais Reguladoras e Acessórias/genética , Filoviridae/patogenicidade , Infecções por Filoviridae/patologia , Infecções por Filoviridae/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/genética , Interferon Tipo I/antagonistas & inibidores , Biologia Molecular/métodos , Transdução de Sinais/efeitos dos fármacos
6.
Methods Mol Biol ; 1628: 195-202, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28573621

RESUMO

Observation of molecular processes inside living cells is fundamental to a deeper understanding of virus-host interactions in filoviral-infected cells. These observations can provide spatiotemporal insights into protein synthesis, protein-protein interaction dynamics, and transport processes of these highly pathogenic viruses. Thus, live-cell imaging provides the possibility for antiviral screening in real time and gives mechanistic insights into understanding filovirus assembly steps that are dependent on cellular factors, which then represent potential targets against this highly fatal disease. Here we describe analysis of living filovirus-infected cells under maximum biosafety (i.e., BSL4) conditions using plasmid-driven expression of fluorescently labeled viral and cellular proteins and/or viral genome-encoded expression of fluorescently labeled proteins. Such multiple-color and multidimensional time-lapse live-cell imaging analyses are a powerful method to gain a better understanding of the filovirus infection cycle.


Assuntos
Infecções por Filoviridae/diagnóstico por imagem , Filoviridae/isolamento & purificação , Interações Hospedeiro-Patógeno , Imagem Molecular/métodos , Linhagem Celular , Contenção de Riscos Biológicos , Filoviridae/patogenicidade , Infecções por Filoviridae/virologia , Humanos
7.
PLoS One ; 12(5): e0178224, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28542463

RESUMO

Reston virus (family Filoviridae) is unique among the viruses of the Ebolavirus genus in that it is considered non-pathogenic in humans, in contrast to the other members which are highly virulent. The virus has however, been associated with several outbreaks of highly lethal hemorrhagic fever in non-human primates (NHPs), specifically cynomolgus monkeys (Macaca fascicularis) originating in the Philippines. In addition, Reston virus has been isolated from domestic pigs in the Philippines. To better understand virus spillover events and potential adaption to new hosts, the whole genome sequences of representative Reston virus isolates were obtained using a next generation sequencing (NGS) approach and comparative genomic analysis and virus fitness analyses were performed. Nine virus genome sequences were completed for novel and previously described isolates obtained from a variety of hosts including a human case, non-human primates and pigs. Results of phylogenetic analysis of the sequence differences are consistent with multiple independent introductions of RESTV from a still unknown natural reservoir into non-human primates and swine farming operations. No consistent virus genetic markers were found specific for viruses associated with primate or pig infections, but similar to what had been seen with some Ebola viruses detected in the large Western Africa outbreak in 2014-2016, a truncated version of VP30 was identified in a subgroup of Reston viruses obtained from an outbreak in pigs 2008-2009. Finally, the genetic comparison of two closely related viruses, one isolated from a human case and one from an NHP, showed amino acid differences in the viral polymerase and detectable differences were found in competitive growth assays on human and NHP cell lines.


Assuntos
Filoviridae/genética , Genoma Viral/genética , Animais , Surtos de Doenças/veterinária , Ebolavirus/genética , Ebolavirus/patogenicidade , Filoviridae/patogenicidade , Infecções por Filoviridae/veterinária , Infecções por Filoviridae/virologia , Marcadores Genéticos/genética , Doença pelo Vírus Ebola/veterinária , Doença pelo Vírus Ebola/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Macaca fascicularis/virologia , Suínos/virologia
8.
Sci Transl Med ; 9(384)2017 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-28381540

RESUMO

As observed during the 2013-2016 Ebola virus disease epidemic, containment of filovirus outbreaks is challenging and made more difficult by the lack of approved vaccine or therapeutic options. Marburg and Ravn viruses are highly virulent and cause severe and frequently lethal disease in humans. Monoclonal antibodies (mAbs) are a platform technology in wide use for autoimmune and oncology indications. Previously, we described human mAbs that can protect mice from lethal challenge with Marburg virus. We demonstrate that one of these mAbs, MR191-N, can confer a survival benefit of up to 100% to Marburg or Ravn virus-infected rhesus macaques when treatment is initiated up to 5 days post-inoculation. These findings extend the small but growing body of evidence that mAbs can impart therapeutic benefit during advanced stages of disease with highly virulent viruses and could be useful in epidemic settings.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Infecções por Filoviridae/tratamento farmacológico , Filoviridae/fisiologia , Doença do Vírus de Marburg/tratamento farmacológico , Marburgvirus/fisiologia , Animais , Proteção Cruzada , Infecções por Filoviridae/virologia , Cobaias , Humanos , Macaca fascicularis , Macaca mulatta , Doença do Vírus de Marburg/virologia , Projetos Piloto
9.
Emerg Infect Dis ; 23(3): 482-486, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28221123

RESUMO

Genetically divergent filoviruses detected in Rousettus and Eonycteris spp. bats in China exhibited 61%-99% nt identity with reported filoviruses, based on partial replicase sequences, and they demonstrated lung tropism. Co-infection with 4 different filoviruses was found in 1 bat. These results demonstrate that fruit bats are key reservoirs of filoviruses.


Assuntos
Quirópteros/virologia , Infecções por Filoviridae/veterinária , Filoviridae/genética , Variação Genética , Animais , China/epidemiologia , Filoviridae/isolamento & purificação , Infecções por Filoviridae/epidemiologia , Infecções por Filoviridae/virologia , Humanos
10.
Antiviral Res ; 135: 1-14, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27640102

RESUMO

This review focuses on the recent progress in our understanding of filovirus protein structure/function and its impact on antiviral research. Here we focus on the surface glycoprotein GP1,2 and its different roles in filovirus entry. We first describe the latest advances on the characterization of GP gene-overlapping proteins sGP, ssGP and Δ-peptide. Then, we compare filovirus surface GP1,2 proteins in terms of structure, synthesis and function. As they bear potential in drug-design, the discovery of small organic compounds inhibiting filovirus entry is a currently very active field. Although it is at an early stage, the development of antiviral drugs against Ebola and Marburg virus entry might prove essential to reduce outbreak-associated fatality rates through post-exposure treatment of both suspected and confirmed cases.


Assuntos
Antivirais , Descoberta de Drogas , Filoviridae/efeitos dos fármacos , Filoviridae/fisiologia , Glicoproteínas/metabolismo , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Ebolavirus/química , Filoviridae/química , Filoviridae/patogenicidade , Infecções por Filoviridae/tratamento farmacológico , Infecções por Filoviridae/virologia , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/química , Humanos , Marburgvirus/química , Camundongos , Proteínas do Envelope Viral/antagonistas & inibidores , Proteínas do Envelope Viral/química
11.
J Infect Dis ; 214(suppl 3): S250-S257, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27638946

RESUMO

BACKGROUND: A unit of the European Mobile Laboratory (EMLab) consortium was deployed to the Ebola virus disease (EVD) treatment unit in Guéckédou, Guinea, from March 2014 through March 2015. METHODS: The unit diagnosed EVD and malaria, using the RealStar Filovirus Screen reverse transcription-polymerase chain reaction (RT-PCR) kit and a malaria rapid diagnostic test, respectively. RESULTS: The cleaned EMLab database comprised 4719 samples from 2741 cases of suspected EVD from Guinea. EVD was diagnosed in 1231 of 2178 hospitalized patients (57%) and in 281 of 563 who died in the community (50%). Children aged <15 years had the highest proportion of Ebola virus-malaria parasite coinfections. The case-fatality ratio was high in patients aged <5 years (80%) and those aged >74 years (90%) and low in patients aged 10-19 years (40%). On admission, RT-PCR analysis of blood specimens from patients who died in the hospital yielded a lower median cycle threshold (Ct) than analysis of blood specimens from survivors (18.1 vs 23.2). Individuals who died in the community had a median Ct of 21.5 for throat swabs. Multivariate logistic regression on 1047 data sets revealed that low Ct values, ages of <5 and ≥45 years, and, among children aged 5-14 years, malaria parasite coinfection were independent determinants of a poor EVD outcome. CONCLUSIONS: Virus load, age, and malaria parasite coinfection play a role in the outcome of EVD.


Assuntos
Ebolavirus/isolamento & purificação , Epidemias , Infecções por Filoviridae/diagnóstico , Doença pelo Vírus Ebola/diagnóstico , Malária/complicações , Unidades Móveis de Saúde , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Serviços de Laboratório Clínico , Ebolavirus/genética , Feminino , Filoviridae , Infecções por Filoviridae/complicações , Infecções por Filoviridae/virologia , Guiné , Doença pelo Vírus Ebola/complicações , Doença pelo Vírus Ebola/virologia , Humanos , Lactente , Malária/parasitologia , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga Viral , Adulto Jovem
12.
J Infect Dis ; 214(suppl 3): S243-S249, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27549586

RESUMO

BACKGROUND: Diagnosis of Ebola virus (EBOV) disease (EVD) requires laboratory testing. METHODS: The RealStar Filovirus Screen reverse transcription-polymerase chain reaction (RT-PCR) kit and the derived RealStar Zaire Ebolavirus RT-PCR kit were validated using in vitro transcripts, supernatant of infected cell cultures, and clinical specimens from patients with EVD. RESULTS: The Filovirus Screen kit detected EBOV, Sudan virus, Taï Forest virus, Bundibugyo virus, Reston virus, and Marburg virus and differentiated between the genera Ebolavirus and Marburgvirus The amount of filovirus RNA that could be detected with a probability of 95% ranged from 11 to 67 RNA copies/reaction on a LightCycler 480 II. The Zaire Ebolavirus kit is based on the Filovirus Screen kit but was optimized for detection of EBOV. It has an improved signal-to-noise ratio at low EBOV RNA concentrations and is somewhat more sensitive than the Filovirus kit. Both kits show significantly lower analytical sensitivity on a SmartCycler II. Clinical evaluation revealed that the SmartCycler II, compared with other real-time PCR platforms, decreases the clinical sensitivity of the Filovirus Screen kit to diagnose EVD at an early stage. CONCLUSIONS: The Filovirus Screen kit detects all human-pathogenic filoviruses with good analytical sensitivity if performed on an appropriate real-time PCR platform. High analytical sensitivity is important for early diagnosis of EVD.


Assuntos
Ebolavirus/isolamento & purificação , Infecções por Filoviridae/diagnóstico , Filoviridae/isolamento & purificação , Doença pelo Vírus Ebola/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Ebolavirus/genética , Filoviridae/genética , Infecções por Filoviridae/virologia , Doença pelo Vírus Ebola/virologia , Humanos , Patologia Molecular , RNA Viral/análise , RNA Viral/genética , Kit de Reagentes para Diagnóstico , Sensibilidade e Especificidade
13.
J Virol ; 90(20): 9209-23, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27489269

RESUMO

UNLABELLED: Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. IMPORTANCE: The 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics.


Assuntos
Ebolavirus/imunologia , Furões/virologia , Infecções por Filoviridae/microbiologia , Filoviridae/imunologia , África Ocidental , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Feminino , Infecções por Filoviridae/virologia , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Humanos , Vacinas Virais/imunologia
14.
J Infect Dis ; 214(suppl 3): S297-S302, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27354372

RESUMO

Filoviruses are strongly associated with several species of bats as their natural reservoirs. In this study, we determined the replication potential of all filovirus species: Marburg marburgvirus, Taï Forest ebolavirus, Reston ebolavirus, Sudan ebolavirus, Zaire ebolavirus, and Bundibugyo ebolavirus. Filovirus replication was supported by all cell lines derived from 6 Old and New World bat species: the hammer-headed fruit bat, Buettikofer's epauletted fruit bat, the Egyptian fruit bat, the Jamaican fruit bat, the Mexican free-tailed bat and the big brown bat. In addition, we showed that Marburg virus Angola and Ebola virus Makona-WPGC07 efficiently replicated at 37°C, 37°-41°C, or 41°C, contrary to the hypothesis that temporal elevation in temperature due to flight affects filovirus replication in bats.


Assuntos
Quirópteros/virologia , Reservatórios de Doenças/virologia , Infecções por Filoviridae/virologia , Filoviridae/isolamento & purificação , Doença pelo Vírus Ebola/virologia , Doença do Vírus de Marburg/virologia , Animais , Linhagem Celular , Ebolavirus/imunologia , Ebolavirus/isolamento & purificação , Ebolavirus/fisiologia , Filoviridae/fisiologia , Humanos , Marburgvirus/imunologia , Marburgvirus/isolamento & purificação , Marburgvirus/fisiologia , Temperatura Ambiente , Replicação Viral
15.
FEMS Microbiol Rev ; 40(4): 494-519, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27268907

RESUMO

Eight viruses are currently assigned to the family Filoviridae Marburg virus, Sudan virus and, in particular, Ebola virus have received the most attention both by researchers and the public from 1967 to 2013. During this period, natural human filovirus disease outbreaks occurred sporadically in Equatorial Africa and, despite high case-fatality rates, never included more than several dozen to a few hundred infections per outbreak. Research emphasis shifted almost exclusively to Ebola virus in 2014, when this virus was identified as the cause of an outbreak that has thus far involved more than 28 646 people and caused more than 11 323 deaths in Western Africa. Consequently, major efforts are currently underway to develop licensed medical countermeasures against Ebola virus infection. However, the ecology of and mechanisms behind Ebola virus emergence are as little understood as they are for all other filoviruses. Consequently, the possibility of the future occurrence of a large disease outbreak caused by other less characterized filoviruses (i.e. Bundibugyo virus, Lloviu virus, Ravn virus, Reston virus and Taï Forest virus) is impossible to rule out. Yet, for many of these viruses, not even rudimentary research tools are available, let alone medical countermeasures. This review summarizes the current knowledge on these less well-characterized filoviruses.


Assuntos
Doenças Transmissíveis Emergentes/virologia , Infecções por Filoviridae/virologia , Doenças Negligenciadas/virologia , África/epidemiologia , Doenças Transmissíveis Emergentes/epidemiologia , Doenças Transmissíveis Emergentes/prevenção & controle , Surtos de Doenças/prevenção & controle , Filoviridae , Infecções por Filoviridae/epidemiologia , Infecções por Filoviridae/prevenção & controle , Humanos , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/prevenção & controle
16.
J Mol Biol ; 428(17): 3449-66, 2016 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-27189922

RESUMO

Ebola, Marburg, and Ravn viruses, all filoviruses, are the causative agents of severe hemorrhagic fever. Much of what we understand about the pathogenesis of filovirus disease is derived from work with animal models, including nonhuman primates, which are considered the "gold standard" filovirus model since they faithfully recapitulate the clinical hallmarks of filovirus disease. However, rodent models, including the mouse, guinea pig, and hamster, also exist for Ebola, Marburg, and Ravn viruses, and although they may not reproduce all the clinical signs of filovirus disease, thanks to their relative ease of use and low cost, they are often the first choice for initial descriptions of virus pathogenesis and evaluation of antiviral prophylactics and therapeutics. Since filoviruses do not cause significant disease in adult, immunocompetent rodents, these models rely on "rodent-adapted" viruses that have been passaged several times through their host until virulence and lethality are achieved. In the process of adaptation, the viruses acquire numerous nucleotide/amino acid mutations that contribute to virulence in their rodent host. Interestingly, virus protein 24 (VP24) and nucleoprotein (NP) appear to be major virulence factors for ebolaviruses in rodents, whereas VP40 appears to be the major virulence factor for marburgviruses. By characterizing these mutations and understanding the molecular mechanisms that lead to the acquisition of virulence, we can gain better insight into the pathogenic processes that underlie filovirus disease in humans. These processes, and the viral and/or cellular proteins that contribute to them, will make attractive targets for the development of novel therapeutics and counter-measures.


Assuntos
Adaptação Biológica , Modelos Animais de Doenças , Infecções por Filoviridae/patologia , Infecções por Filoviridae/virologia , Filoviridae/genética , Filoviridae/patogenicidade , Animais , Cricetinae , Cobaias , Camundongos , Virulência
17.
Artigo em Inglês | MEDLINE | ID: mdl-27103629

RESUMO

The Ebola outbreak of 2013-15 infected more than 28 000 people and claimed more lives than all previous filovirus outbreaks combined. Governmental agencies, clinical teams, and the world scientific community pulled together in a multifaceted response ranging from prevention and disease control, to evaluating vaccines and therapeutics in human trials. As this epidemic is finally coming to a close, refocusing on long-term prevention strategies becomes paramount. Given the very real threat of future filovirus outbreaks, and the inherent uncertainty of the next outbreak virus and geographic location, it is prudent to consider the extent and implications of known natural diversity in advancing vaccines and therapeutic approaches. To facilitate such consideration, we have updated and enhanced the content of the filovirus portion of Los Alamos Hemorrhagic Fever Viruses Database. We have integrated and performed baseline analysis of all family ITALIC! Filoviridaesequences deposited into GenBank, with associated immune response data, and metadata, and we have added new computational tools with web-interfaces to assist users with analysis. Here, we (i) describe the main features of updated database, (ii) provide integrated views and some basic analyses summarizing evolutionary patterns as they relate to geo-temporal data captured in the database and (iii) highlight the most conserved regions in the proteome that may be useful for a T cell vaccine strategy.Database URL:www.hfv.lanl.gov.


Assuntos
Bases de Dados Genéticas , Infecções por Filoviridae/virologia , Filoviridae/genética , Filoviridae/imunologia , Infecções por Filoviridae/imunologia , Humanos , Internet , New Mexico , Interface Usuário-Computador
18.
Viruses ; 7(10): 5172-90, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26426036

RESUMO

The family Filoviridae contains several of the most deadly pathogens known to date and the current Ebola virus disease (EVD) outbreak in Western Africa, due to Ebola virus (EBOV) infection, highlights the need for active and broad research into filovirus pathogenesis. However, in comparison, the seven other known filovirus family members are significantly understudied. Many of these, including Marburgviruses and Ebolaviruses other than EBOV, are also highly virulent and fully capable of causing widespread epidemics. This review places the focus on these non-EBOV filoviruses, including known immunological and pathological data. The available animal models, research tools and currently available therapeutics will also be discussed along with an emphasis in the large number of current gaps in knowledge of these less highlighted filoviruses. It is evident that much research is yet to be done in order to bring the non-EBOV filovirus field to the forefront of current research and, importantly, to the development of more effective vaccines and therapeutics to combat potential future outbreaks.


Assuntos
Infecções por Filoviridae/epidemiologia , Infecções por Filoviridae/virologia , Filoviridae/fisiologia , Animais , Pesquisa Biomédica/tendências , Modelos Animais de Doenças , Surtos de Doenças , Filoviridae/imunologia , Filoviridae/patogenicidade , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/patologia , Humanos , Virulência
19.
J Infect Dis ; 212 Suppl 2: S384-8, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-25957964

RESUMO

The filoviruses, Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SEBOV), cause severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Monovalent recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode a filovirus glycoprotein (GP) in place of the VSV glycoprotein, have shown 100% efficacy against homologous filovirus challenge in rodent and NHP studies. Here, we examined the utility of a single-vector, single-injection trivalent rVSV vector expressing MARV, ZEBOV, and SEBOV GPs to protect against MARV-, ZEBOV-, and SEBOV-induced disease in outbred Hartley guinea pigs where we observed protection from effects of all 3 filoviruses.


Assuntos
Infecções por Filoviridae/imunologia , Filoviridae/imunologia , Vetores Genéticos/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/imunologia , Feminino , Infecções por Filoviridae/virologia , Glicoproteínas/imunologia , Cobaias , Vesiculovirus/imunologia
20.
J Infect Dis ; 212 Suppl 2: S404-9, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26022440

RESUMO

Stat1(-/-) mice lack a response to interferon α, ß, and γ, allowing for replication of nonadapted wild-type (wt) Ebolavirus and Marburgvirus. We sought to establish a mouse model for efficacy testing of live attenuated recombinant vesicular stomatitis virus (rVSV)-based filovirus vaccine vectors using wt Ebolavirus and Marburgvirus challenge strains. While infection of immunocompetent mice with different rVSV-based filovirus vectors did not cause disease, infection of Stat1(-/-) mice with the same vectors resulted in systemic infection and lethal outcome for the majority of tested rVSVs. Despite differences in viral loads, organ tropism was remarkably similar between rVSV filovirus vaccine vectors and rVSVwt, with the exception of the brain. In conclusion, Stat1(-/-) mice are not an appropriate immunocompromised mouse model for efficacy testing of live attenuated, replication-competent rVSV vaccine vectors.


Assuntos
Filoviridae/imunologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Vacinas Atenuadas/imunologia , Estomatite Vesicular/imunologia , Vacinas Virais/imunologia , Animais , Cercopithecus aethiops , Modelos Animais de Doenças , Ebolavirus/imunologia , Infecções por Filoviridae/genética , Infecções por Filoviridae/imunologia , Infecções por Filoviridae/virologia , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/virologia , Doença do Vírus de Marburg/genética , Doença do Vírus de Marburg/imunologia , Doença do Vírus de Marburg/virologia , Marburgvirus/imunologia , Camundongos , Fator de Transcrição STAT1/imunologia , Células Vero , Carga Viral/imunologia , Replicação Viral/genética , Replicação Viral/imunologia
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