Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 260
Filtrar
1.
Nat Commun ; 11(1): 3849, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737300

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58-7.12)), HIV positivity (OR = 2.22(1.32-3.73)) and living in a more rural area (OR = 1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10-09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10-12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10-44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.


Assuntos
Anticorpos Antivirais/biossíntese , Resistência à Doença/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Henipavirus/genética , Interações Hospedeiro-Patógeno/genética , Sarcoma de Kaposi/genética , Adolescente , Adulto , Antígenos Virais/genética , Antígenos Virais/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Coinfecção , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , HIV/genética , HIV/imunologia , HIV/patogenicidade , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População Rural , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Uganda/epidemiologia , População Urbana
2.
Am J Trop Med Hyg ; 103(3): 1241-1246, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32588798

RESUMO

In any outbreak situation, a poor stakeholder response can impede the outbreak control and can have high economic and social cost. We conducted a qualitative study to understand stakeholder response in handling of the Nipah deceased persons during the outbreak of Nipah in Kerala, 2018. To understand the responses and to generate knowledge from the data, we used grounded theory approach for the study and conducted in-depth interviews and focus group discussion. Mixed public response and swift state response emerged as the main themes in our study. Under the "mixed public response," three categories emerged, including anxiety and fear, conflicting religious beliefs, and humanitarian concern. Under the "swift state response," the categories emerged were critical resources and robust guidance. A collective effort involving the administration, local and religious groups, and a culturally acceptable scientific protocol proved to be good examples of gaining social acceptance. Kerala puts forth a model of efficient community engagement and communication to gain public support and acceptance in a fatal disease outbreak.


Assuntos
Surtos de Doenças , Infecções por Henipavirus/epidemiologia , Vírus Nipah/isolamento & purificação , Feminino , Grupos Focais , Infecções por Henipavirus/virologia , Humanos , Índia/epidemiologia , Masculino , Pesquisa Qualitativa
3.
J Infect Dis ; 221(Supplement_4): S480-S492, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32037447

RESUMO

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis and respiratory disease in humans. There is currently no approved therapeutic for human use against NiV infection. Griffithsin (GRFT) is high-mannose oligosaccharide binding lectin that has shown in vivo broad-spectrum activity against viruses, including severe acute respiratory syndrome coronavirus, human immunodeficiency virus 1, hepatitis C virus, and Japanese encephalitis virus. In this study, we evaluated the in vitro antiviral activities of GRFT and its synthetic trimeric tandemer (3mG) against NiV and other viruses from 4 virus families. The 3mG had comparatively greater potency than GRFT against NiV due to its enhanced ability to block NiV glycoprotein-induced syncytia formation. Our initial in vivo prophylactic evaluation of an oxidation-resistant GRFT (Q-GRFT) showed significant protection against lethal NiV challenge in Syrian golden hamsters. Our results warrant further development of Q-GRFT and 3mG as potential NiV therapeutics.


Assuntos
Antivirais/farmacologia , Infecções por Henipavirus/tratamento farmacológico , Vírus Nipah/efeitos dos fármacos , Lectinas de Plantas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Chlorocebus aethiops , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HEK293 , Células HeLa , Infecções por Henipavirus/virologia , Humanos , Mesocricetus , Vírus Nipah/isolamento & purificação , Lectinas de Plantas/uso terapêutico , Células Vero
4.
Sci Rep ; 10(1): 1477, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001794

RESUMO

The G-quadruplex (GQ) motifs are considered as potential drug-target sites for several human pathogenic viruses such as Zika, Hepatitis, Ebola, and Human Herpesviruses. The recent outbreaks of Nipah virus (NiV) in India, the highly fatal emerging zoonotic virus is a potential threat to global health security as no anti-viral drug or vaccine in currently available. Therefore, here in the present study, we sought to assess the ability of the putative G-quadruplex forming sequences in the NiV genome to form G-quadruplex structures and act as targets for anti-viral compounds. Bioinformatics analysis underpinned by various biophysical and biochemical techniques (such as NMR, CD, EMSA, DMS footprinting assay) confirmed the presence of two highly conserved G-quadruplex forming sequences (HGQs) in the G and L genes of NiV. These genes encode the cell attachment glycoprotein and RNA-dependent RNA polymerase, respectively and are essential for the virus entry and replication within the host cell. It remains possible that stabilization of these HGQs by the known G-quadruplex binding ligands like TMPyP4 and Braco-19 represents a promising strategy to inhibit the expression of the HGQ harboring genes and thereby stop the viral entry and replication inside the host cell. Accordingly, we report for the first time, that HGQs in Nipah virus genome are targets for G-quadruplex specific ligands; therefore, could serve as potential targets for anti-viral therapy.


Assuntos
Quadruplex G , Genoma Viral , Vírus Nipah/genética , Acridinas/farmacologia , Antivirais/farmacologia , Biologia Computacional , Sequência Conservada , Quadruplex G/efeitos dos fármacos , Infecções por Henipavirus/virologia , Humanos , Ligação de Hidrogênio , Índia , Ligantes , Vírus Nipah/efeitos dos fármacos , Vírus Nipah/fisiologia , Porfirinas/farmacologia , Internalização do Vírus , Replicação Viral
5.
Database (Oxford) ; 20202020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32090261

RESUMO

Nipah virus (NiV) is an emerging and priority pathogen from the Paramyxoviridae family with a high fatality rate. It causes various diseases such as respiratory ailments and encephalitis and poses a great threat to humans and livestock. Despite various efforts, there is no approved antiviral treatment available. Therefore, to expedite and assist the research, we have developed an integrative resource NipahVR (http://bioinfo.imtech.res.in/manojk/nipahvr/) for the multi-targeted putative therapeutics and epitopes for NiV. It is structured into different sections, i.e. genomes, codon usage, phylogenomics, molecular diagnostic primers, therapeutics (siRNAs, sgRNAs, miRNAs) and vaccine epitopes (B-cell, CTL, MHC-I and -II binders). Most decisively, potentially efficient therapeutic regimens targeting different NiV proteins and genes were anticipated and projected. We hope this computational resource would be helpful in developing combating strategies against this deadly pathogen. Database URL: http://bioinfo.imtech.res.in/manojk/nipahvr/.


Assuntos
Bases de Dados Genéticas , Infecções por Henipavirus , Vírus Nipah , Animais , Antivirais , Epitopos/genética , Genoma Viral/genética , Infecções por Henipavirus/tratamento farmacológico , Infecções por Henipavirus/virologia , Humanos , Patologia Molecular , Filogenia , RNA não Traduzido/genética , RNA Viral/genética
6.
Transbound Emerg Dis ; 67(1): 121-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31408582

RESUMO

Since its first emergence in 1998 in Malaysia, Nipah virus (NiV) has become a great threat to domestic animals and humans. Sporadic outbreaks associated with human-to-human transmission caused hundreds of human fatalities. Here, we collected all available NiV sequences and combined phylogenetics, molecular selection, structural biology and receptor analysis to study the emergence and adaptive evolution of NiV. NiV can be divided into two main lineages including the Bangladesh and Malaysia lineages. We formly confirmed a significant association with geography which is probably the result of long-term evolution of NiV in local bat population. The two NiV lineages differ in many amino acids; one change in the fusion protein might be involved in its activation via binding to the G protein. We also identified adaptive and positively selected sites in many viral proteins. In the receptor-binding G protein, we found that sites 384, 386 and especially 498 of G protein might modulate receptor-binding affinity and thus contribute to the host jump from bats to humans via the adaption to bind the human ephrin-B2 receptor. We also found that site 1645 in the connector domain of L was positive selected and involved in adaptive evolution; this site might add methyl groups to the cap structure present at the 5'-end of the RNA and thus modulate its activity. This study provides insight to assist the design of early detection methods for NiV to assess its epidemic potential in humans.


Assuntos
Adaptação Biológica , Quirópteros/virologia , Surtos de Doenças , Infecções por Henipavirus/virologia , Vírus Nipah/genética , Polimorfismo Genético , Animais , Bangladesh/epidemiologia , Evolução Biológica , Biologia Computacional , Geografia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/transmissão , Especificidade de Hospedeiro , Humanos , Malásia/epidemiologia , Modelos Moleculares , Vírus Nipah/isolamento & purificação , Vírus Nipah/patogenicidade , Vírus Nipah/fisiologia , Filogenia , Proteínas Virais/genética
7.
Sci Rep ; 9(1): 16710, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31723221

RESUMO

Nipah virus (NiV) is a pathogenic paramyxovirus and zoononis with very high human fatality rates. Previous protein over-expression studies have shown that various mutations to the common N-terminal STAT1-binding motif of the NiV P, V, and W proteins affected the STAT1-binding ability of these proteins thus interfering with he JAK/STAT pathway and reducing their ability to inhibit type-I IFN signaling, but due to differing techniques it was unclear which amino acids were most important in this interaction or what impact this had on pathogenesis in vivo. We compared all previously described mutations in parallel and found the amino acid mutation Y116E demonstrated the greatest reduction in binding to STAT1 and the greatest reduction in interferon antagonism. A similar reduction in binding and activity was seen for a deletion of twenty amino acids constituting the described STAT1-binding domain. To investigate the contribution of this STAT1-binding motif in NiV-mediated disease, we produced rNiVs with complete deletion of the STAT1-binding motif or the Y116E mutation for ferret challenge studies (rNiVM-STAT1blind). Despite the reduced IFN inhibitory function, ferrets challenged with these rNiVM-STAT1blind mutants had a lethal, albeit altered, NiV-mediated disease course. These data, together with our previously published data, suggest that the major role of NiV P, V, and W in NiV-mediated disease in the ferret model are likely to be in the inhibition of viral recognition/innate immune signaling induction with a minor role for inhibition of IFN signaling.


Assuntos
Infecções por Henipavirus/patologia , Infecções por Henipavirus/virologia , Vírus Nipah/fisiologia , Fosfoproteínas/metabolismo , Fator de Transcrição STAT1/antagonistas & inibidores , Proteínas Virais/metabolismo , Proteínas Estruturais Virais/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , Modelos Animais de Doenças , Progressão da Doença , Feminino , Furões , Infecções por Henipavirus/metabolismo , Fosfoproteínas/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Proteínas Virais/genética , Proteínas Estruturais Virais/genética
8.
Nat Struct Mol Biol ; 26(10): 980-987, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570878

RESUMO

Nipah virus (NiV) and Hendra virus (HeV) are zoonotic henipaviruses (HNVs) responsible for outbreaks of encephalitis and respiratory illness with fatality rates of 50-100%. No vaccines or licensed therapeutics currently exist to protect humans against NiV or HeV. HNVs enter host cells by fusing the viral and cellular membranes via the concerted action of the attachment (G) and fusion (F) glycoproteins, the main targets of the humoral immune response. Here, we describe the isolation and humanization of a potent monoclonal antibody cross-neutralizing NiV and HeV. Cryo-electron microscopy, triggering and fusion studies show the antibody binds to a prefusion-specific quaternary epitope, conserved in NiV F and HeV F glycoproteins, and prevents membrane fusion and viral entry. This work supports the importance of the HNV prefusion F conformation for eliciting a robust immune response and paves the way for using this antibody for prophylaxis and post-exposure therapy with NiV- and HeV-infected individuals.


Assuntos
Anticorpos Neutralizantes/farmacologia , Antivirais/farmacologia , Vírus Hendra/efeitos dos fármacos , Infecções por Henipavirus/tratamento farmacológico , Vírus Nipah/efeitos dos fármacos , Proteínas Virais de Fusão/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Células HEK293 , Vírus Hendra/metabolismo , Infecções por Henipavirus/metabolismo , Infecções por Henipavirus/virologia , Humanos , Modelos Moleculares , Vírus Nipah/metabolismo , Proteínas Virais de Fusão/metabolismo , Internalização do Vírus/efeitos dos fármacos
9.
Proc Natl Acad Sci U S A ; 116(41): 20707-20715, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548390

RESUMO

Cedar virus (CedV) is a bat-borne henipavirus related to Nipah virus (NiV) and Hendra virus (HeV), zoonotic agents of fatal human disease. CedV receptor-binding protein (G) shares only ∼30% sequence identity with those of NiV and HeV, although they can all use ephrin-B2 as an entry receptor. We demonstrate that CedV also enters cells through additional B- and A-class ephrins (ephrin-B1, ephrin-A2, and ephrin-A5) and report the crystal structure of the CedV G ectodomain alone and in complex with ephrin-B1 or ephrin-B2. The CedV G receptor-binding site is structurally distinct from other henipaviruses, underlying its capability to accommodate additional ephrin receptors. We also show that CedV can enter cells through mouse ephrin-A1 but not human ephrin-A1, which differ by 1 residue in the key contact region. This is evidence of species specific ephrin receptor usage by a henipavirus, and implicates additional ephrin receptors in potential zoonotic transmission.


Assuntos
Efrina-B1/metabolismo , Efrina-B2/metabolismo , Efrina-B3/metabolismo , Infecções por Henipavirus/virologia , Henipavirus/fisiologia , Receptores Virais/metabolismo , Proteínas do Envelope Viral/química , Animais , Fusão Celular , Efrina-B1/genética , Efrina-B2/genética , Efrina-B3/genética , Infecções por Henipavirus/genética , Infecções por Henipavirus/metabolismo , Humanos , Camundongos , Mutação , Ligação Proteica , Conformação Proteica , Receptores Virais/genética , Especificidade da Espécie , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus
10.
Philos Trans R Soc Lond B Biol Sci ; 374(1782): 20190021, 2019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31401962

RESUMO

Pathogen circulation among reservoir hosts is a precondition for zoonotic spillover. Unlike the acute, high morbidity infections typical in spillover hosts, infected reservoir hosts often exhibit low morbidity and mortality. Although it has been proposed that reservoir host infections may be persistent with recurrent episodes of shedding, direct evidence is often lacking. We construct a generalized SEIR (susceptible, exposed, infectious, recovered) framework encompassing 46 sub-models representing the full range of possible transitions among those four states of infection and immunity. We then use likelihood-based methods to fit these models to nine years of longitudinal data on henipavirus serology from a captive colony of Eidolon helvum bats in Ghana. We find that reinfection is necessary to explain observed dynamics; that acute infectious periods may be very short (hours to days); that immunity, if present, lasts about 1-2 years; and that recurring latent infection is likely. Although quantitative inference is sensitive to assumptions about serology, qualitative predictions are robust. Our novel approach helps clarify mechanisms of viral persistence and circulation in wild bats, including estimated ranges for key parameters such as the basic reproduction number and the duration of the infectious period. Our results inform how future field-based and experimental work could differentiate the processes of viral recurrence and reinfection in reservoir hosts. This article is part of the theme issue 'Dynamic and integrative approaches to understanding pathogen spillover'.


Assuntos
Quirópteros , Reservatórios de Doenças/veterinária , Infecções por Henipavirus/veterinária , Henipavirus/fisiologia , Animais , Animais de Zoológico , Reservatórios de Doenças/virologia , Gana/epidemiologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/transmissão , Infecções por Henipavirus/virologia , Prevalência , Estudos Soroepidemiológicos
11.
Sci Rep ; 9(1): 11171, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371748

RESUMO

Nipah virus (NiV) has emerged as a highly lethal zoonotic paramyxovirus that is capable of causing a febrile encephalitis and/or respiratory disease in humans for which no vaccines or licensed treatments are currently available. There are two genetically and geographically distinct lineages of NiV: NiV-Malaysia (NiV-M), the strain that caused the initial outbreak in Malaysia, and NiV-Bangladesh (NiV-B), the strain that has been implicated in subsequent outbreaks in India and Bangladesh. NiV-B appears to be both more lethal and have a greater propensity for person-to-person transmission than NiV-M. Here we describe the generation and characterization of stable RNA polymerase II-driven infectious cDNA clones of NiV-M and NiV-B. In vitro, reverse genetics-derived NiV-M and NiV-B were indistinguishable from a wildtype isolate of NiV-M, and both viruses were pathogenic in the Syrian hamster model of NiV infection. We also describe recombinant NiV-M and NiV-B with enhanced green fluorescent protein (EGFP) inserted between the G and L genes that enable rapid and sensitive detection of NiV infection in vitro. This panel of molecular clones will enable studies to investigate the virologic determinants of henipavirus pathogenesis, including the pathogenic differences between NiV-M and NiV-B, and the high-throughput screening of candidate therapeutics.


Assuntos
Vírus Nipah/genética , Animais , Bangladesh , Surtos de Doenças , Infecções por Henipavirus/transmissão , Infecções por Henipavirus/virologia , Humanos , Malásia , Mesocricetus/virologia , RNA Polimerase II , Genética Reversa
12.
JCI Insight ; 4(14)2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31341108

RESUMO

Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes highly lethal henipavirus encephalitis in humans. Survivors develop various neurologic sequelae, including late-onset and relapsing encephalitis, several months up to several years following initial infection. However, the underlying pathology and disease mechanisms of persistent neurologic complications remain unknown. Here, we demonstrate persistent NiV infection in the brains of grivets that survived experimental exposure to NiV. Encephalitis affected the entire brains, with the majority of NiV detected in the neurons and microglia of the brainstems, cerebral cortices, and cerebella. We identified the vascular endothelium in the brain as an initial target of NiV infection during the acute phase of disease, indicating a primary path of entry for NiV into the brain. Notably, we were unable to detect NiV anywhere else except the brains in the examined survivors. Our findings indicate that late-onset and relapsing encephalitis of NiV in human survivors may be due to viral persistence in the brain and shed light on the pathogenesis of chronic henipavirus encephalitis.


Assuntos
Encéfalo/virologia , Doenças Transmissíveis Emergentes/patologia , Infecções por Henipavirus/patologia , Vírus Nipah/isolamento & purificação , Zoonoses/patologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Chlorocebus aethiops , Doença Crônica , Doenças Transmissíveis Emergentes/mortalidade , Doenças Transmissíveis Emergentes/virologia , Modelos Animais de Doenças , Endotélio Vascular/patologia , Endotélio Vascular/virologia , Infecções por Henipavirus/mortalidade , Infecções por Henipavirus/virologia , Humanos , Masculino , Vírus Nipah/patogenicidade , Recidiva , Sobreviventes , Zoonoses/mortalidade , Zoonoses/virologia
13.
Sci Transl Med ; 11(494)2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142680

RESUMO

Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Infecções por Henipavirus/tratamento farmacológico , Infecções por Henipavirus/virologia , Vírus Nipah/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Encéfalo/patologia , Encéfalo/virologia , Chlorocebus aethiops , Feminino , Infecções por Henipavirus/sangue , Masculino , Meningoencefalite/tratamento farmacológico , Meningoencefalite/virologia , Testes de Neutralização , Viremia/sangue , Viremia/tratamento farmacológico , Viremia/virologia , Replicação Viral/efeitos dos fármacos
14.
Emerg Infect Dis ; 25(6): 1144-1152, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31107231

RESUMO

Nipah virus (NiV) is a zoonotic pathogen that causes high case-fatality rates (CFRs) in humans. Two NiV strains have caused outbreaks: the Malaysia strain (NiVM), discovered in 1998-1999 in Malaysia and Singapore (≈40% CFR); and the Bangladesh strain (NiVB), discovered in Bangladesh and India in 2001 (≈80% CFR). Recently, NiVB in African green monkeys resulted in a more severe and lethal disease than NiVM. No NiV vaccines or treatments are licensed for human use. We assessed replication-restricted single-injection recombinant vesicular stomatitis vaccine NiV vaccine vectors expressing the NiV glycoproteins against NiVB challenge in African green monkeys. All vaccinated animals survived to the study endpoint without signs of NiV disease; all showed development of NiV F Ig, NiV G IgG, or both, as well as neutralizing antibody titers. These data show protective efficacy against a stringent and relevant NiVB model of human infection.


Assuntos
Chlorocebus aethiops , Infecções por Henipavirus/veterinária , Vírus Nipah , Vesiculovirus/imunologia , Vacinas Virais/imunologia , Zoonoses , Animais , Feminino , Infecções por Henipavirus/mortalidade , Infecções por Henipavirus/prevenção & controle , Infecções por Henipavirus/virologia , Humanos , Imunidade Humoral , Masculino , Doenças dos Macacos/patologia , Doenças dos Macacos/virologia , Carga Viral
15.
J Virol ; 93(13)2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30971473

RESUMO

Nipah and Hendra viruses (NiV and HeV) exhibit high lethality in humans and are biosafety level 4 (BSL-4) paramyxoviruses in the growing genus Henipavirus The attachment (G) and fusion (F) envelope glycoproteins are both required for viral entry into cells and for cell-cell fusion, which is pathognomonic of henipaviral infections. Here, we compared the fusogenic capacities between homologous and heterologous pairs of NiV and HeV glycoproteins. Importantly, to accurately measure their fusogenic capacities, as these depend on glycoprotein cell surface expression (CSE) levels, we inserted identical extracellular tags to both fusion (FLAG tags) or both attachment (hemagglutinin [HA] tags) glycoproteins. Importantly, these tags were placed in extracellular sites where they did not affect glycoprotein expression or function. NiV and HeV glycoproteins induced comparable levels of homologous HEK293T cell-cell fusion. Surprisingly, however, while the heterologous NiV F/HeV G (NF/HG) combination yielded a hypofusogenic phenotype, the heterologous HeV F/NiV G (HF/NG) combination yielded a hyperfusogenic phenotype. Pseudotyped viral entry levels primarily corroborated the fusogenic phenotypes of the glycoprotein pairs analyzed. Furthermore, we constructed G and F chimeras that allowed us to map the overall regions in G and F that contributed to these hyperfusogenic or hypofusogenic phenotypes. Importantly, the fusogenic phenotypes of the glycoprotein combinations negatively correlated with the avidities of F-G interactions, supporting the F/G dissociation model of henipavirus-induced membrane fusion, even in the context of heterologous glycoprotein pairs.IMPORTANCE The NiV and HeV henipaviruses are BSL-4 pathogens transmitted from bats. NiV and HeV often lead to human death and animal diseases. The formation of multinucleated cells (syncytia) is a hallmark of henipaviral infections and is caused by fusion of cells coordinated by interactions of the viral attachment (G) and fusion (F) glycoproteins. We found via various assays that viral entry and syncytium formation depend on the viral origin of the glycoproteins, with HeV F and NiV G promoting higher membrane fusion levels than their counterparts. This is important knowledge, since both viruses use the same bat vector species and potential coinfections of these or subsequent hosts may alter the outcome of disease.


Assuntos
Glicoproteínas/metabolismo , Vírus Hendra/fisiologia , Infecções por Henipavirus/virologia , Vírus Nipah/fisiologia , Fenótipo , Proteínas Virais de Fusão/fisiologia , Células Gigantes/metabolismo , Glicoproteínas/genética , Células HEK293 , Vírus Hendra/genética , Humanos , Fusão de Membrana , Vírus Nipah/genética , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/fisiologia , Proteínas Virais de Fusão/genética , Ligação Viral , Internalização do Vírus
16.
Emerg Infect Dis ; 25(5): 1003-1006, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31002049

RESUMO

We retrieved Nipah virus (NiV) sequences from 4 human and 3 fruit bat (Pteropus medius) samples from a 2018 outbreak in Kerala, India. Phylogenetic analysis demonstrated that NiV from humans was 96.15% similar to a Bangladesh strain but 99.7%-100% similar to virus from Pteropus spp. bats, indicating bats were the source of the outbreak.


Assuntos
Quirópteros/virologia , Surtos de Doenças , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/virologia , Vírus Nipah/classificação , Vírus Nipah/genética , Animais , Células Cultivadas , Efeito Citopatogênico Viral , Infecções por Henipavirus/história , Infecções por Henipavirus/transmissão , História do Século XXI , Humanos , Índia/epidemiologia , Mutação , Vigilância em Saúde Pública
18.
Vector Borne Zoonotic Dis ; 19(7): 455-465, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30985268

RESUMO

Nipah virus (NiV) and Hendra virus (HeV) are closely related members within the genus Henipavirus, family Paramyxoviridae, for which fruit bats serve as the reservoir. The initial emergence of NiV infections in pigs and humans in Malaysia, and HeV infections in horses and humans in Australia, posed severe impacts on human and animal health, and continues threatening lives of humans and livestock within Southeast Asia and Australia. Recently, henipavirus-specific antibodies have also been detected in fruit bats in a number of sub-Saharan African countries and in Brazil, thereby considerably increasing the known geographic distribution of henipaviruses. Africa is progressively being recognized as a new high prevalence zone for henipaviruses, as deduced from serological and molecular evidence of past infections in Madagascar, Ghana, Republic of Congo, Gulf of Guinea, Zambia, Tanzania, Cameroon, and Nigeria lately. Serological data suggest henipavirus spillover from bats to livestock and human populations in Africa without reported clinical disease in any of these species. All virus isolation attempts have been abortive, highlighting the need for further investigations. The genome of the Ghanaian bat henipavirus designated Ghana virus (GhV), which was detected in a pteropid Eidolon helvum bat, is the only African henipavirus that has been completely sequenced limiting our current knowledge on the genetic diversity and pathogenesis of African henipaviruses. In this review, we summarize the available data on the circulation of henipaviruses in Africa, discuss potential sources for virus spillover, and highlight existing research gaps.


Assuntos
Quirópteros/virologia , Infecções por Henipavirus/epidemiologia , Henipavirus , África/epidemiologia , Animais , Anticorpos Antivirais , Infecções por Henipavirus/veterinária , Infecções por Henipavirus/virologia , Humanos , Gado/virologia , Estudos Soroepidemiológicos , Zoonoses/virologia
19.
Pathog Dis ; 77(2)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30985897

RESUMO

Nipah virus (NiV) and Hendra virus are highly pathogenic zoonotic viruses of the genus Henipavirus, family Paramyxoviridae. These viruses were first identified as the causative agents of severe respiratory and encephalitic disease in the 1990s across Australia and Southern Asia with mortality rates reaching up to 75%. While outbreaks of Nipah and Hendra virus infections remain rare and sporadic, there is concern that NiV has pandemic potential. Despite increased attention, little is understood about the neuropathogenesis of henipavirus infection. Neuropathogenesis appears to arise from dual mechanisms of vascular disease and direct parenchymal brain infection, but the relative contributions remain unknown while respiratory disease arises from vasculitis and respiratory epithelial cell infection. This review will address NiV basic clinical disease, pathology and pathogenesis with a particular focus on central nervous system (CNS) infection and address the necessity of a model of relapsed CNS infection. Additionally, the innate immune responses to NiV infection in vitro and in the CNS are reviewed as it is likely linked to any persistent CNS infection.


Assuntos
Viroses do Sistema Nervoso Central/virologia , Infecções por Henipavirus/virologia , Henipavirus/fisiologia , Doença Aguda , Idade de Início , Animais , Viroses do Sistema Nervoso Central/diagnóstico , Viroses do Sistema Nervoso Central/epidemiologia , Viroses do Sistema Nervoso Central/transmissão , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infecções por Henipavirus/diagnóstico , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/transmissão , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata
20.
J Neurovirol ; 25(4): 475-479, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31028690

RESUMO

There are only few documented cases of progressive multifocal leukoencephalopathy (PML) in Africa. Whether this is caused by a lack of JC virus (JCV) spread or alteration in the JCV genome is unknown. We characterized the clinical presentation, laboratory findings, and JCV regulatory region (RR) pattern of the first documented PML cases in Zambia as well as JCV seroprevalence among HIV+ and HIV- Zambians. We identified PML patients with positive JCV DNA PCR in their cerebrospinal fluid (CSF) among subjects enrolled in an ongoing tuberculous meningitis study from 2014 to 2016 in Lusaka. JCV regulatory region was further characterized by duplex PCR in patients' urine and CSF. Of 440 HIV+ patients, 14 (3%) had detectable JCV DNA in their CSF (age 18-50; CD4+ T cells counts 15-155 × 106/µl) vs 0/60 HIV- patients. The main clinical manifestations included altered mental status and impaired consciousness consistent with advanced PML. While prototype JCV was identified by duplex PCR assay in the CSF samples of all 14 PML patients, only archetype JCV was detected in their urine. All PML Zambian patients tested were seropositive for JCV compared to 46% in a control group of HIV+ and HIV- Zambian patients without PML. PML occurs among HIV-infected individuals in Zambia and is caused by CNS infection with prototype JCV, while archetype JCV strains are present in their urine. JCV seroprevalence is comparable in Zambia and the USA, and PML should be included in the differential diagnosis of immunosuppressed individuals presenting with neurological dysfunction in Zambia.


Assuntos
DNA Viral/genética , Infecções por Henipavirus/diagnóstico , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Tuberculose Meníngea/diagnóstico , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Coinfecção , DNA Viral/líquido cefalorraquidiano , DNA Viral/urina , Feminino , Genótipo , HIV/efeitos dos fármacos , HIV/genética , HIV/isolamento & purificação , Infecções por Henipavirus/líquido cefalorraquidiano , Infecções por Henipavirus/tratamento farmacológico , Infecções por Henipavirus/virologia , Humanos , Vírus JC/efeitos dos fármacos , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/líquido cefalorraquidiano , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Tuberculose Meníngea/líquido cefalorraquidiano , Tuberculose Meníngea/tratamento farmacológico , Tuberculose Meníngea/virologia , Zâmbia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...