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2.
Biol Lett ; 15(12): 20190423, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31822244

RESUMO

Sampling reservoir hosts over time and space is critical to detect epizootics, predict spillover and design interventions. However, because sampling is logistically difficult and expensive, researchers rarely perform spatio-temporal sampling of many reservoir hosts. Bats are reservoirs of many virulent zoonotic pathogens such as filoviruses and henipaviruses, yet the highly mobile nature of these animals has limited optimal sampling of bat populations. To quantify the frequency of temporal sampling and to characterize the geographical scope of bat virus research, we here collated data on filovirus and henipavirus prevalence and seroprevalence in wild bats. We used a phylogenetically controlled meta-analysis to next assess temporal and spatial variation in bat virus detection estimates. Our analysis shows that only one in four bat virus studies report data longitudinally, that sampling efforts cluster geographically (e.g. filovirus data are available across much of Africa and Asia but are absent from Latin America and Oceania), and that sampling designs and reporting practices may affect some viral detection estimates (e.g. filovirus seroprevalence). Within the limited number of longitudinal bat virus studies, we observed high heterogeneity in viral detection estimates that in turn reflected both spatial and temporal variation. This suggests that spatio-temporal sampling designs are important to understand how zoonotic viruses are maintained and spread within and across wild bat populations, which in turn could help predict and preempt risks of zoonotic viral spillover.


Assuntos
Quirópteros , Filoviridae , Henipavirus , África , Animais , Ásia , Estudos Soroepidemiológicos
3.
Vet Microbiol ; 237: 108405, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31561922

RESUMO

Nipah virus (NiV), a BSL-4 pathogen, belongs to the genus Henipavirus within the family Paramyxoviridae. To date, no effective vaccine is available. Although most of the current vaccine studies aim to induce a neutralizing antibody response, it has become evident that a promising vaccine should target both, humoral and cell-mediated immune response. Virus-like particles (VLPs) have been shown to activate both arms of the adaptive immune response. In our study, VLPs composed of the NiV surface glycoproteins G and F and the matrix protein of the closely related Hendra virus (HeV M) induced both, a neutralizing antibody response and an antigen-specific CD8 T cell response with proliferation, IFN-γ expression and Th1 cytokine secretion in C57BL/6 mice. In contrast, in BALB/c mice only a neutralizing antibody response was observed. All three viral proteins included in the VLPs were shown to harbor CD8 T cell epitopes; however, the combination of all three proteins enhanced the magnitude of the CD8 T cell response. To conclude, VLPs represent a promising vaccine candidate, as they induce humoral as well as CD8 T cell-mediated immune responses.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/fisiologia , Proliferação de Células/fisiologia , Henipavirus/imunologia , Proteínas Virais/imunologia , Animais , Anticorpos Neutralizantes , Chlorocebus aethiops , Citocinas , Regulação da Expressão Gênica/imunologia , Células HEK293 , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Plasmídeos , Baço/citologia , Células Th1 , Células Th2 , Células Vero , Proteínas Virais/genética
4.
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
5.
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
6.
Viruses ; 11(3)2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909389

RESUMO

Syrian hamsters (Mesocricetus auratus) are a pathogenesis model for the Nipah virus (NiV), and we sought to determine if they are also susceptible to the Cedar virus (CedPV). Following intranasal inoculation with CedPV, virus replication occurred in the lungs and spleens of infected hamsters, a neutralizing antibody was produced in some hamsters within 8 days post-challenge, and no conspicuous signs of disease occurred. CedPV replicated to a similar magnitude as NiV-Bangladesh in type I IFN-deficient BHK-21 Syrian hamster fibroblasts but replicated 4 logs lower in type I IFN-competent primary Syrian hamster and human pulmonary endothelial cells, a principal target of henipaviruses. The coinfection of these cells with CedPV and NiV failed to rescue CedPV titers and did not diminish NiV titers, suggesting the replication machinery is virus-specific. Type I IFN response transcripts Ifna7, Ddx58, Stat1, Stat2, Ccl5, Cxcl10, Isg20, Irf7, and Iigp1 were all significantly elevated in CedPV-infected hamster endothelial cells, whereas Ifna7 and Iigp1 expression were significantly repressed during NiV infection. These results are consistent with the hypothesis that CedPV's inability to counter the host type I IFN response may, in part, contribute to its lack of pathogenicity. Because NiV causes a fatal disease in Syrian hamsters with similarities to human disease, this model will provide valuable information about the pathogenic mechanisms of henipaviruses.


Assuntos
Infecções por Henipavirus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Replicação Viral , Animais , Coinfecção/imunologia , Coinfecção/virologia , Cricetinae , Células Endoteliais/imunologia , Células Endoteliais/virologia , Feminino , Henipavirus/patogenicidade , Henipavirus/fisiologia , Humanos , Pulmão/virologia , Vírus Nipah/patogenicidade , Vírus Nipah/fisiologia , Baço/virologia
7.
Viruses ; 10(11)2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388838

RESUMO

Hendra virus (HeV) and Nipah virus (NiV) are among a group of emerging bat-borne paramyxoviruses that have crossed their species-barrier several times by infecting several hosts with a high fatality rate in human beings. Despite the fatal nature of their infection, a comprehensive study to explore their evolution and adaptation in different hosts is lacking. A study of codon usage patterns in henipaviruses may provide some fruitful insight into their evolutionary processes of synonymous codon usage and host-adapted evolution. Here, we performed a systematic evolutionary and codon usage bias analysis of henipaviruses. We found a low codon usage bias in the coding sequences of henipaviruses and that natural selection, mutation pressure, and nucleotide compositions shapes the codon usage patterns of henipaviruses, with natural selection being more important than the others. Also, henipaviruses showed the highest level of adaptation to bats of the genus Pteropus in the codon adaptation index (CAI), relative to the codon de-optimization index (RCDI), and similarity index (SiD) analyses. Furthermore, a comparison to recently identified henipa-like viruses indicated a high tRNA adaptation index of henipaviruses for human beings, mainly due to F, G and L proteins. Consequently, the study concedes the substantial emergence of henipaviruses in human beings, particularly when paired with frequent exposure to direct/indirect bat excretions.


Assuntos
Códon , Evolução Molecular , Infecções por Henipavirus/virologia , Henipavirus/genética , Especificidade de Hospedeiro , Interações Hospedeiro-Patógeno , Seleção Genética , Adaptação Biológica , Animais , Quirópteros/virologia , Genoma Viral , Genômica/métodos , Henipavirus/classificação , Humanos , Filogenia
8.
Nat Commun ; 9(1): 3057, 2018 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-30076298

RESUMO

Recent studies indicate that nucleoli play critical roles in the DNA-damage response (DDR) via interaction of DDR machinery including NBS1 with nucleolar Treacle protein, a key mediator of ribosomal RNA (rRNA) transcription and processing. Here, using proteomics, confocal and single molecule super-resolution imaging, and infection under biosafety level-4 containment, we show that this nucleolar DDR pathway is targeted by infectious pathogens. We find that the matrix proteins of Hendra virus and Nipah virus, highly pathogenic viruses of the Henipavirus genus in the order Mononegavirales, interact with Treacle and inhibit its function, thereby silencing rRNA biogenesis, consistent with mimicking NBS1-Treacle interaction during a DDR. Furthermore, inhibition of Treacle expression/function enhances henipavirus production. These data identify a mechanism for viral modulation of host cells by appropriating the nucleolar DDR and represent, to our knowledge, the first direct intranucleolar function for proteins of any mononegavirus.


Assuntos
Nucléolo Celular/fisiologia , Nucléolo Celular/virologia , Dano ao DNA/fisiologia , Vírus Hendra/fisiologia , Vírus Nipah/fisiologia , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Células HeLa , Henipavirus/genética , Infecções por Henipavirus , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Mononegavirais/genética , Proteínas Nucleares/metabolismo , Nucleoproteínas/metabolismo , Proteômica , RNA Ribossômico/biossíntese , Proteínas Virais/metabolismo
9.
Vet Microbiol ; 218: 90-97, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29685227

RESUMO

Hendra virus (HeV) and Nipah virus (NiV) are highly pathogenic henipaviruses originating from fruit bats in Australia and Asia that can cause severe infections in livestock and humans. In recent years, also African bat henipaviruses were identified at the nucleic acid level. To assess their potential to replicate in non-bat species, several studies were performed to characterize the two surface glycoproteins required for virus entry and spread by cell-cell fusion. It has been shown that surface expression and fusion-helper function of the receptor-binding G protein of Kumasi virus (KV), the prototypic Ghanaian bat henipavirus, is reduced compared to other non-African henipavirus G proteins. Immunostainings and pulse-chase analysis revealed a delayed export of KV G from the ER. As defects in oligomerization of viral glycoproteins can be responsible for limited surface transport thereby restricting the bioactivity, we analyzed the oligomerization pattern of KV G. In contrast to HeV and NiV whose G proteins are known to be expressed at a dimer-tetramer ratio of 1:1, KV G almost exclusively formed stable tetramers or higher oligomers. KV G also showed less stringent requirements for defined stalk cysteines to form dimers and tetramers. Interestingly, any changes in the oligomeric forms negatively affected the fusion-helper activity although surface expression and receptor binding was unchanged. This clearly indicates that the formation of mostly higher oligomeric KV G forms is not a deficiency responsible for ER retention, but is rather a basic structural feature essential for the bioactivity of this African bat henipavirus glycoprotein.


Assuntos
Quirópteros/virologia , Proteínas de Ligação ao GTP/química , Henipavirus/metabolismo , Glicoproteínas de Membrana/química , Proteínas do Envelope Viral , Animais , Retículo Endoplasmático/virologia , Proteínas de Ligação ao GTP/metabolismo , Gana/epidemiologia , Henipavirus/química , Henipavirus/genética , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/virologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Internalização do Vírus
10.
Antiviral Res ; 153: 101-113, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29601894

RESUMO

Ebolaviruses, marburgviruses, and henipaviruses are zoonotic pathogens belonging to the Filoviridae and Paramyxoviridae families. They exemplify viruses that continue to spill over into the human population, causing outbreaks characterized by high mortality and significant clinical sequelae in survivors of infection. There are currently no approved small molecule therapeutics for use in humans against these viruses. In this study, we evaluated the antiviral activity of the nucleoside analog 4'-azidocytidine (4'N3-C, R1479) and its 2'-monofluoro- and 2'-difluoro-modified analogs (2'F-4'N3-C and 2'diF-4'N3-C) against representative paramyxoviruses (Nipah virus, Hendra virus, measles virus, and human parainfluenza virus 3) and filoviruses (Ebola virus, Sudan virus, and Ravn virus). We observed enhanced antiviral activity against paramyxoviruses with both 2'diF-4'N3-C and 2'F-4'N3-C compared to R1479. On the other hand, while R1479 and 2'diF-4'N3-C inhibited filoviruses similarly to paramyxoviruses, we observed 10-fold lower filovirus inhibition by 2'F-4'N3-C. To our knowledge, this is the first study to compare the susceptibility of paramyxoviruses and filoviruses to R1479 and its 2'-fluoro-modified analogs. The activity of these compounds against negative-strand RNA viruses endorses the development of 4'-modified nucleoside analogs as broad-spectrum therapeutics against zoonotic viruses of public health importance.


Assuntos
Antivirais/farmacologia , Citidina/análogos & derivados , Ebolavirus/efeitos dos fármacos , Henipavirus/efeitos dos fármacos , Marburgvirus/efeitos dos fármacos , Citidina/farmacologia , Testes de Sensibilidade Microbiana
11.
Vet J ; 233: 25-34, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29486875

RESUMO

Bat-borne viruses carry undeniable risks to the health of human beings and animals, and there is growing recognition of the need for a 'One Health' approach to understand their frequently complex spill-over routes. While domesticated animals can play central roles in major spill-over events of zoonotic bat-borne viruses, for example during the pig-amplified Malaysian Nipah virus outbreak of 1998-1999, the extent of their potential to act as bridging or amplifying species for these viruses has not been characterised systematically. This review aims to compile current knowledge on the role of domesticated animals as hosts of two types of bat-borne viruses, henipaviruses and filoviruses. A systematic literature search of these virus-host interactions in domesticated animals identified 72 relevant studies, which were categorised by year, location, design and type of evidence generated. The review then focusses on Africa as a case study, comparing research efforts in domesticated animals and bats with the distributions of documented human cases. Major gaps remain in our knowledge of the potential ability of domesticated animals to contract or spread these zoonoses. Closing these gaps will be necessary to fully evaluate and mitigate spill-over risks of these viruses, especially with global agricultural intensification.


Assuntos
Animais Domésticos/virologia , Quirópteros/virologia , Reservatórios de Doenças/virologia , Filoviridae , Henipavirus , África/epidemiologia , Animais , Infecções por Filoviridae/transmissão , Infecções por Filoviridae/veterinária , Infecções por Henipavirus/transmissão , Infecções por Henipavirus/veterinária , Humanos , Zoonoses/transmissão , Zoonoses/virologia
12.
PLoS Negl Trop Dis ; 12(3): e0006343, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29538374

RESUMO

Henipavirus infection causes severe respiratory and neurological disease in humans that can be fatal. To characterize the pathogenic mechanisms of henipavirus infection in vivo, we performed experimental infections in ferrets followed by genome-wide gene expression analysis of lung and brain tissues. The Hendra, Nipah-Bangladesh, and Nipah-Malaysia strains caused severe respiratory and neurological disease with animals succumbing around 7 days post infection. Despite the presence of abundant viral shedding, animal-to-animal transmission did not occur. The host gene expression profiles of the lung tissue showed early activation of interferon responses and subsequent expression of inflammation-related genes that coincided with the clinical deterioration. Additionally, the lung tissue showed unchanged levels of lymphocyte markers and progressive downregulation of cell cycle genes and extracellular matrix components. Infection in the brain resulted in a limited breadth of the host responses, which is in accordance with the immunoprivileged status of this organ. Finally, we propose a model of the pathogenic mechanisms of henipavirus infection that integrates multiple components of the host responses.


Assuntos
Infecções por Henipavirus/genética , Infecções por Henipavirus/imunologia , Henipavirus/fisiologia , Interações Hospedeiro-Patógeno , Transcriptoma , Animais , Encéfalo/metabolismo , Encéfalo/virologia , Ciclo Celular , Modelos Animais de Doenças , Matriz Extracelular/genética , Furões/virologia , Vírus Hendra/imunologia , Vírus Hendra/patogenicidade , Henipavirus/genética , Infecções por Henipavirus/virologia , Humanos , Inflamação , Interferons/genética , Pulmão/metabolismo , Pulmão/virologia , Vírus Nipah/imunologia , Vírus Nipah/patogenicidade , Eliminação de Partículas Virais
13.
Virol J ; 15(1): 56, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29587789

RESUMO

BACKGROUND: Hendra virus and Nipah virus are zoonotic viruses that have caused severe to fatal disease in livestock and human populations. The isolation of Cedar virus, a non-pathogenic virus species in the genus Henipavirus, closely-related to the highly pathogenic Hendra virus and Nipah virus offers an opportunity to investigate differences in pathogenesis and receptor tropism among these viruses. METHODS: We constructed full-length cDNA clones of Cedar virus from synthetic oligonucleotides and rescued two replication-competent, recombinant Cedar virus variants: a recombinant wild-type Cedar virus and a recombinant Cedar virus that expresses a green fluorescent protein from an open reading frame inserted between the phosphoprotein and matrix genes. Replication kinetics of both viruses and stimulation of the interferon pathway were characterized in vitro. Cellular tropism for ephrin-B type ligands was qualitatively investigated by microscopy and quantitatively by a split-luciferase fusion assay. RESULTS: Successful rescue of recombinant Cedar virus expressing a green fluorescent protein did not significantly affect virus replication compared to the recombinant wild-type Cedar virus. We demonstrated that recombinant Cedar virus stimulated the interferon pathway and utilized the established Hendra virus and Nipah virus receptor, ephrin-B2, but not ephrin-B3 to mediate virus entry. We further characterized virus-mediated membrane fusion kinetics of Cedar virus with the known henipavirus receptors ephrin-B2 and ephrin-B3. CONCLUSIONS: The recombinant Cedar virus platform may be utilized to characterize the determinants of pathogenesis across the henipaviruses, investigate their receptor tropisms, and identify novel pan-henipavirus antivirals. Moreover, these experiments can be conducted safely under BSL-2 conditions.


Assuntos
Efrina-B2/metabolismo , Infecções por Henipavirus/virologia , Henipavirus/fisiologia , Receptores Virais/metabolismo , Fusão Celular , Linhagem Celular , Efeito Citopatogênico Viral , Genes Reporter , Proteínas de Fluorescência Verde/genética , Henipavirus/genética , Henipavirus/metabolismo , Henipavirus/patogenicidade , Infecções por Henipavirus/metabolismo , Interferon Tipo I/genética , Testes de Neutralização , Ligação Proteica , Recombinação Genética , Genética Reversa , Proteínas do Envelope Viral/metabolismo , Tropismo Viral , Internalização do Vírus , Replicação Viral
14.
PLoS One ; 13(2): e0191933, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29390028

RESUMO

In 2011, an unusually large number of independent Hendra virus outbreaks were recorded on horse properties in Queensland and New South Wales, Australia. Urine from bat colonies adjacent to the outbreak sites were sampled and screened for Hendra and other viruses. Several novel paramyxoviruses were also isolated at different locations. Here one of the novel viruses, named Hervey virus (HerPV), is fully characterized by genome sequencing, annotation, phylogeny and in vitro host range, and its serological cross-reactivity and neutralization patterns are examined. HerPV may have ecological and spatial and temporal patterns similar to Hendra virus and could serve as a sentinel virus for the surveillance of this highly pathogenic virus. The suitability of HerPV as potential sentinel virus is further assessed by determining the serological prevalence of HerPV antibodies in fruit-eating bats from Australia, Indonesia, Papua New Guinea, Tanzania and the Gulf of Guinea, indicating the presence of similar viruses in regions beyond the Australian border.


Assuntos
Quirópteros/virologia , Henipavirus/isolamento & purificação , Paramyxovirinae/isolamento & purificação , África/epidemiologia , Animais , Anticorpos Antivirais/imunologia , Austrália/epidemiologia , Linhagem Celular , Surtos de Doenças , Henipavirus/genética , Henipavirus/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Indonésia/epidemiologia , Microscopia Confocal , Testes de Neutralização , Papua Nova Guiné/epidemiologia , Paramyxovirinae/genética , Paramyxovirinae/imunologia
15.
Mol Biosyst ; 13(11): 2254-2267, 2017 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-28972216

RESUMO

Henipaviruses are severe human pathogens within the Paramyxoviridae family. Beyond the P protein, the Henipavirus P gene also encodes the V protein which shares with P its N-terminal, intrinsically disordered region (PNT) and possesses a unique C-terminal domain predicted to be folded and to bind zinc (ZnFD). Henipavirus V proteins antagonize IFN signaling through PNT-mediated binding to STAT1, and several paramyxoviral V proteins promote STAT1 degradation through binding to DDB1. Structural and molecular information on Henipavirus V proteins is lacking, and their ability to interact with DDB1 has not been documented yet. We cloned the V genes from Nipah and Hendra viruses and purified the V proteins from E. coli and DDB1 from insect cells. Using analytical size-exclusion chromatography, CD and SAXS we characterized the V proteins and their domains. Using pull-down and MST we assessed their binding abilities towards DDB1. We show that PNT remains disordered also in the context of the V protein, while the ZnFD adopts a predominant ß conformation. We also show that the V proteins interact with DDB1 predominantly via their ZnFD. This is the first experimental characterization of the Henipavirus V proteins and the first experimental evidence of their interaction with DDB1. The DDB1-ZnFD interaction constitutes a promising target for antiviral strategies. These studies provide a conceptual asset to design new antiviral strategies expected to reduce or abrogate the ability of these viruses to escape the innate immune response. They also contribute to illuminating the conformational behaviour of proteins encompassing large intrinsically disordered domains.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Henipavirus/metabolismo , Domínios e Motivos de Interação entre Proteínas , Desdobramento de Proteína , Proteínas Virais/química , Proteínas Virais/metabolismo , Dedos de Zinco , Sequência de Aminoácidos , Dicroísmo Circular , Interações Hidrofóbicas e Hidrofílicas , Espectrometria de Massas , Ligação Proteica , Proteínas Recombinantes , Espectrofotometria Ultravioleta , Proteínas Virais/genética , Proteínas Virais/isolamento & purificação , Difração de Raios X
16.
J Gen Virol ; 98(4): 563-576, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28056216

RESUMO

Viruses of the genus Henipavirus of the family Paramyxoviridae are zoonotic pathogens, which have emerged in Southeast Asia, Australia and Africa. Nipah virus (NiV) and Hendra virus are highly virulent pathogens transmitted from bats to animals and humans, while the henipavirus Cedar virus seems to be non-pathogenic in infection studies. The full replication cycle of the Paramyxoviridae occurs in the host cell's cytoplasm, where viral assembly is orchestrated by the matrix (M) protein. Unexpectedly, the NiV-M protein traffics through the nucleus as an essential step to engage the plasma membrane in preparation for viral budding/release. Comparative studies were performed to assess whether M protein nuclear localization is a common feature of the henipaviruses, including the recently sequenced (although not yet isolated) Ghanaian bat henipavirus (Kumasi virus, GH-M74a virus) and Mojiang virus. Live-cell confocal microscopy revealed that nuclear translocation of GFP-fused M protein is conserved between henipaviruses in both human- and bat-derived cell lines. However, the efficiency of M protein nuclear localization and virus-like particle budding competency varied. Additionally, Cedar virus-, Kumasi virus- and Mojiang virus-M proteins were mutated in a bipartite nuclear localization signal, indicating that a key lysine residue is essential for nuclear import, export and induction of budding events, as previously reported for NiV-M. The results of this study suggest that the M proteins of henipaviruses may utilize a similar nucleocytoplasmic trafficking pathway as an essential step during viral replication in both humans and bats.


Assuntos
Transporte Ativo do Núcleo Celular , Henipavirus/genética , Henipavirus/fisiologia , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/metabolismo , Animais , Henipavirus/isolamento & purificação , Humanos , Microscopia Confocal , Microscopia de Fluorescência , Sinais de Localização Nuclear , Transporte Proteico , Virossomos/genética , Virossomos/metabolismo
17.
Int Rev Immunol ; 36(2): 108-121, 2017 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-28060559

RESUMO

Hendra virus and Nipah virus (NiV) are highly pathogenic zoonotic paramyxoviruses, from henipavirus genus, that have emerged in late 1990s in Australia and South-East Asia, respectively. Since their initial identification, numerous outbreaks have been reported, affecting both domestic animals and humans, and multiple rounds of person-to-person NiV transmission were observed. Widely distributed fruit bats from Pteropodidae family were found to be henipavirus natural reservoir. Numerous studies have reported henipavirus seropositivity in pteropid bats, including bats in Africa, thus expanding notably the geographic distribution of these viruses. Interestingly, henipavirus infection in bats seems to be asymptomatic, in contrast to severe disease induced in numerous other mammals. Unique among the mammals by their ability to fly, these intriguing animals are natural reservoir for many other emerging and remerging viruses highly pathogenic for humans. This feature, combined with absence of clinical symptoms, has attracted the interest of scientific community to virus-bat interactions. Therefore, several bat genomes were sequenced and particularities of the bat immune system have been intensively analyzed during the last decade to understand their coexistence with viruses in the absence of disease. The peculiarities in inflammasome activation, a constitutive expression of interferon alpha, and some differences in adaptive immunity have been recently reported in fruit bats. Studies on virus-bat interactions have thus emerged as an exciting novel area of research that should shed new light on the mechanisms that regulate viral infection and may allow development of novel therapeutic approaches to control this highly lethal emerging infectious disease in humans.


Assuntos
Quirópteros/imunologia , Infecções por Henipavirus/imunologia , Henipavirus/fisiologia , Animais , Portador Sadio , Quirópteros/virologia , Reservatórios de Doenças/virologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade , Controle de Infecções , Inflamassomos/metabolismo , Interferon-alfa/metabolismo
18.
Vector Borne Zoonotic Dis ; 17(4): 271-274, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28103156

RESUMO

Bats are reservoir hosts for many paramyxoviruses, some of which cause human and zoonotic diseases of public health importance. We developed a Nipah virus nucleoprotein enzyme-linked immunosorbent assay to detect cross-reactive antibodies in serum samples from several bat species in Brazil. Our results warrant further investigation of henipa-like virus reservoirs in the Western hemisphere.


Assuntos
Quirópteros/virologia , Infecções por Henipavirus/veterinária , Henipavirus/imunologia , Animais , Brasil/epidemiologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/virologia
19.
PLoS Pathog ; 12(10): e1005974, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27783670

RESUMO

Hendra and Nipah viruses (family Paramyxoviridae, genus Henipavirus) are bat-borne viruses that cause fatal disease in humans and a range of other mammalian species. Gaining a deeper understanding of host pathways exploited by henipaviruses for infection may identify targets for new anti-viral therapies. Here we have performed genome-wide high-throughput agonist and antagonist screens at biosafety level 4 to identify host-encoded microRNAs (miRNAs) impacting henipavirus infection in human cells. Members of the miR-181 and miR-17~93 families strongly promoted Hendra virus infection. miR-181 also promoted Nipah virus infection, but did not affect infection by paramyxoviruses from other genera, indicating specificity in the virus-host interaction. Infection promotion was primarily mediated via the ability of miR-181 to significantly enhance henipavirus-induced membrane fusion. Cell signalling receptors of ephrins, namely EphA5 and EphA7, were identified as novel negative regulators of henipavirus fusion. The expression of these receptors, as well as EphB4, were suppressed by miR-181 overexpression, suggesting that simultaneous inhibition of several Ephs by the miRNA contributes to enhanced infection and fusion. Immune-responsive miR-181 levels was also up-regulated in the biofluids of ferrets and horses infected with Hendra virus, suggesting that the host innate immune response may promote henipavirus spread and exacerbate disease severity. This study is the first genome-wide screen of miRNAs influencing infection by a clinically significant mononegavirus and nominates select miRNAs as targets for future anti-viral therapy development.


Assuntos
Infecções por Henipavirus/genética , MicroRNAs/genética , Internalização do Vírus , Animais , Furões , Imunofluorescência , Estudo de Associação Genômica Ampla , Henipavirus , Sequenciamento de Nucleotídeos em Larga Escala , Cavalos , Humanos , Reação em Cadeia da Polimerase em Tempo Real
20.
Sci Data ; 3: 160049, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27479120

RESUMO

Bats, including African straw-coloured fruit bats (Eidolon helvum), have been highlighted as reservoirs of many recently emerged zoonotic viruses. This common, widespread and ecologically important species was the focus of longitudinal and continent-wide studies of the epidemiological and ecology of Lagos bat virus, henipaviruses and Achimota viruses. Here we present a spatial, morphological, demographic, genetic and serological dataset encompassing 2827 bats from nine countries over an 8-year period. Genetic data comprises cytochrome b mitochondrial sequences (n=608) and microsatellite genotypes from 18 loci (n=544). Tooth-cementum analyses (n=316) allowed derivation of rare age-specific serologic data for a lyssavirus, a henipavirus and two rubulaviruses. This dataset contributes a substantial volume of data on the ecology of E. helvum and its viruses and will be valuable for a wide range of studies, including viral transmission dynamic modelling in age-structured populations, investigation of seasonal reproductive asynchrony in wide-ranging species, ecological niche modelling, inference of island colonisation history, exploration of relationships between island and body size, and various spatial analyses of demographic, morphometric or serological data.


Assuntos
Quirópteros/imunologia , Lyssavirus , Animais , Henipavirus , Nigéria , Rubulavirus
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