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1.
Cell Rep ; 39(11): 110969, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35679864

RESUMO

Emerging infectious diseases, especially if caused by bat-borne viruses, significantly affect public health and the global economy. There is an urgent need to understand the mechanism of interspecies transmission, particularly to humans. Viral genetics; host factors, including polymorphisms in the receptors; and ecological, environmental, and population dynamics are major parameters to consider. Here, we describe the taxonomy, geographic distribution, and unique traits of bats associated with their importance as virus reservoirs. Then, we summarize the origin, intermediate hosts, and the current understanding of interspecies transmission of Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Nipah, Hendra, Ebola, Marburg virus, and rotaviruses. Finally, the molecular interactions of viral surface proteins with host cell receptors are examined, and a comparison of these interactions in humans, intermediate hosts, and bats is conducted. This uncovers adaptive mutations in virus spike protein that facilitate cross-species transmission and risk factors associated with the emergence of novel viruses from bats.


Assuntos
COVID-19 , Quirópteros , Filoviridae , Henipavirus , Rotavirus , Vírus , Animais , Filoviridae/genética , Humanos , Rotavirus/genética , SARS-CoV-2/genética
2.
Int J Mol Sci ; 23(2)2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35055108

RESUMO

Henipaviruses are severe human pathogens within the Paramyxoviridae family. Beyond the P protein, the Henipavirus P gene also encodes the V and W proteins which share with P their N-terminal, intrinsically disordered domain (NTD) and possess a unique C-terminal domain. Henipavirus W proteins antagonize interferon (IFN) signaling through NTD-mediated binding to STAT1 and STAT4, and prevent type I IFN expression and production of chemokines. Structural and molecular information on Henipavirus W proteins is lacking. By combining various bioinformatic approaches, we herein show that the Henipaviruses W proteins are predicted to be prevalently disordered and yet to contain short order-prone segments. Using limited proteolysis, differential scanning fluorimetry, analytical size exclusion chromatography, far-UV circular dichroism and small-angle X-ray scattering, we experimentally confirmed their overall disordered nature. In addition, using Congo red and Thioflavin T binding assays and negative-staining transmission electron microscopy, we show that the W proteins phase separate to form amyloid-like fibrils. The present study provides an additional example, among the few reported so far, of a viral protein forming amyloid-like fibrils, therefore significantly contributing to enlarge our currently limited knowledge of viral amyloids. In light of the critical role of the Henipavirus W proteins in evading the host innate immune response and of the functional role of phase separation in biology, these studies provide a conceptual asset to further investigate the functional impact of the phase separation abilities of the W proteins.


Assuntos
Amiloide/metabolismo , Henipavirus/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo , Benzotiazóis/metabolismo , Dicroísmo Circular , Simulação por Computador , Vermelho Congo/metabolismo , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Modelos Moleculares , Domínios Proteicos , Proteólise , Espalhamento a Baixo Ângulo , Difração de Raios X
3.
Lancet Infect Dis ; 22(1): e13-e27, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34735799

RESUMO

Henipaviruses, including Nipah virus, are regarded as pathogens of notable epidemic potential because of their high pathogenicity and the paucity of specific medical countermeasures to control infections in humans. We review the evidence of medical countermeasures against henipaviruses and project their cost in a post-COVID-19 era. Given the sporadic and unpredictable nature of henipavirus outbreaks, innovative strategies will be needed to circumvent the infeasibility of traditional phase 3 clinical trial regulatory pathways. Stronger partnerships with scientific institutions and regulatory authorities in low-income and middle-income countries can inform coordination of appropriate investments and development of strategies and normative guidelines for the deployment and equitable use of multiple medical countermeasures. Accessible measures should include global, regional, and endemic in-country stockpiles of reasonably priced small molecules, monoclonal antibodies, and vaccines as part of a combined collection of products that could help to control henipavirus outbreaks and prevent future pandemics.


Assuntos
Surtos de Doenças/prevenção & controle , Infecções por Henipavirus/tratamento farmacológico , Henipavirus/patogenicidade , Contramedidas Médicas , Saúde Pública , Animais , COVID-19/prevenção & controle , Quirópteros/virologia , Ensaios Clínicos Fase III como Assunto , Henipavirus/classificação , Infecções por Henipavirus/prevenção & controle , Infecções por Henipavirus/transmissão , Humanos , Vírus Nipah/patogenicidade , SARS-CoV-2/patogenicidade
4.
Sci Rep ; 11(1): 24262, 2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34930962

RESUMO

Bat-borne viruses in the Henipavirus genus have been associated with zoonotic diseases of high morbidity and mortality in Asia and Australia. In Africa, the Egyptian rousette bat species (Rousettus aegyptiacus) is an important viral host in which Henipavirus-related viral sequences have previously been identified. We expanded these findings by assessing the viral dynamics in a southern African bat population. A longitudinal study of henipavirus diversity and excretion dynamics identified 18 putative viral species circulating in a local population, three with differing seasonal dynamics, and the winter and spring periods posing a higher risk of virus spillover and transmission. The annual peaks in virus excretion are most likely driven by subadults and may be linked to the waning of maternal immunity and recolonization of the roost in early spring. These results provide insightful information into the bat-host relationship that can be extrapolated to other populations across Africa and be communicated to at-risk communities as a part of evidence-based public health education and prevention measures against pathogen spillover threats.


Assuntos
Quirópteros/virologia , Reservatórios de Doenças/virologia , Marburgvirus/imunologia , Paramyxoviridae/imunologia , Estações do Ano , África , Animais , Ásia , Austrália , Geografia , Henipavirus , Humanos , Estudos Longitudinais , África do Sul , Fatores de Tempo , Zoonoses/epidemiologia , Zoonoses/virologia
5.
Viruses ; 13(10)2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34696450

RESUMO

Paramyxoviruses, negative-sense single-stranded RNA viruses, pose a critical threat to human public health. Currently, 78 species, 17 genera, and 4 subfamilies of paramyxoviruses are harbored by multiple natural reservoirs, including rodents, bats, birds, reptiles, and fish. Henipaviruses are critical zoonotic pathogens that cause severe acute respiratory distress and neurological diseases in humans. Using reverse transcription-polymerase chain reaction, 115 Crocidura species individuals were examined for the prevalence of paramyxovirus infections. Paramyxovirus RNA was observed in 26 (22.6%) shrews collected at five trapping sites, Republic of Korea. Herein, we report two genetically distinct novel paramyxoviruses (genus: Henipavirus): Gamak virus (GAKV) and Daeryong virus (DARV) isolated from C. lasiura and C. shantungensis, respectively. Two GAKVs and one DARV were nearly completely sequenced using next-generation sequencing. GAKV and DARV contain six genes (3'-N-P-M-F-G-L-5') with genome sizes of 18,460 nucleotides and 19,471 nucleotides, respectively. The phylogenetic inference demonstrated that GAKV and DARV form independent genetic lineages of Henipavirus in Crocidura species. GAKV-infected human lung epithelial cells elicited the induction of type I/III interferons, interferon-stimulated genes, and proinflammatory cytokines. In conclusion, this study contributes further understandings of the molecular prevalence, genetic characteristics and diversity, and zoonotic potential of novel paramyxoviruses in shrews.


Assuntos
Henipavirus/classificação , Henipavirus/genética , Paramyxovirinae/classificação , Paramyxovirinae/genética , Filogenia , Musaranhos/virologia , Animais , Biodiversidade , Aves/virologia , Quirópteros/virologia , Peixes/virologia , Henipavirus/isolamento & purificação , Sequenciamento de Nucleotídeos em Larga Escala , Interferons , Paramyxovirinae/isolamento & purificação , Vírus de RNA/classificação , Répteis/virologia , República da Coreia , Roedores/virologia , Zoonoses Virais/virologia
6.
J Virol Methods ; 298: 114287, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34530012

RESUMO

Henipaviruses, Hendra (HeV) and Nipah (NiV), are highly pathogenic zoonotic agents that pose a serious health risk to human life, and as such are restricted to physical containment 4 (PC4) laboratories. For further analysis of virus-infected biological specimens, it is necessary to ensure absolute inactivation of any infectious virus present before removal from the PC4 laboratory. To evaluate the inactivation of HeV and NiV within infected samples, two chemical inactivation methods were assessed. Henipavirus-infected cell monolayers treated with 4 % paraformaldehyde (PFA) showed the complete inactivation of infectious virus, with an inactivation period of 15 min resulting in more than 8-log decrease in infectious titre. NiV-infected tissue samples treated with 10 % neutral-buffered formalin (NBF) showed a complete reduction of infectious virus in 7/8 ferret organs incubated for 24 h, with the remaining tissue demonstrating complete virus inactivation after 48 h. The chemical inactivation methods described herein evaluated two simple methods of henipavirus inactivation, resulting in the complete inactivation of infectious virus - an essential requirement for the safe removal and handling of biological samples from the PC4 laboratory.


Assuntos
Vírus Hendra , Infecções por Henipavirus , Henipavirus , Vírus Nipah , Animais , Contenção de Riscos Biológicos , Furões , Infecções por Henipavirus/prevenção & controle , Infecções por Henipavirus/veterinária , Humanos , Laboratórios , Vírus Nipah/fisiologia
7.
Cell Rep ; 36(9): 109628, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34469726

RESUMO

Hendra virus and Nipah virus (NiV), members of the Henipavirus (HNV) genus, are zoonotic paramyxoviruses known to cause severe disease across six mammalian orders, including humans. We isolated a panel of human monoclonal antibodies (mAbs) from the B cells of an individual with prior exposure to equine Hendra virus (HeV) vaccine, targeting distinct antigenic sites. The most potent class of cross-reactive antibodies achieves neutralization by blocking viral attachment to the host cell receptors ephrin-B2 and ephrin-B3, with a second class being enhanced by receptor binding. mAbs from both classes display synergistic activity in vitro. In a stringent hamster model of NiV Bangladesh (NiVB) infection, antibodies from both classes reduce morbidity and mortality and achieve synergistic protection in combination. These candidate mAbs might be suitable for use in a cocktail therapeutic approach to achieve synergistic potency and reduce the risk of virus escape.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Antivirais/farmacologia , Efrina-B2/antagonistas & inibidores , Efrina-B3/antagonistas & inibidores , Infecções por Henipavirus/prevenção & controle , Henipavirus/patogenicidade , Receptores Virais/antagonistas & inibidores , Animais , Especificidade de Anticorpos , Chlorocebus aethiops , Reações Cruzadas , Modelos Animais de Doenças , Quimioterapia Combinada , Efrina-B2/imunologia , Efrina-B2/metabolismo , Efrina-B3/imunologia , Efrina-B3/metabolismo , Feminino , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/metabolismo , Infecções por Henipavirus/virologia , Interações Hospedeiro-Patógeno , Humanos , Mesocricetus , Receptores Virais/imunologia , Receptores Virais/metabolismo , Células Vero
8.
Viruses ; 13(7)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34372504

RESUMO

Pandemics are a consequence of a series of processes that span scales from viral biology at 10-9 m to global transmission at 106 m. The pathogen passes from one host species to another through a sequence of events that starts with an infected reservoir host and entails interspecific contact, innate immune responses, receptor protein structure within the potential host, and the global spread of the novel pathogen through the naive host population. Each event presents a potential barrier to the onward passage of the virus and should be characterized with an integrated transdisciplinary approach. Epidemic control is based on the prevention of exposure, infection, and disease. However, the ultimate pandemic prevention is prevention of the spillover event itself. Here, we focus on the potential for preventing the spillover of henipaviruses, a group of viruses derived from bats that frequently cross species barriers, incur high human mortality, and are transmitted among humans via stuttering chains. We outline the transdisciplinary approach needed to prevent the spillover process and, therefore, future pandemics.


Assuntos
Quirópteros/virologia , Saúde Global , Infecções por Henipavirus/prevenção & controle , Henipavirus/patogenicidade , Pandemias/prevenção & controle , Viroses/prevenção & controle , Zoonoses/virologia , Animais , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/transmissão , Especificidade de Hospedeiro , Humanos , Imunidade Inata , Vírus Nipah/patogenicidade , Viroses/imunologia , Viroses/transmissão , Zoonoses/prevenção & controle , Zoonoses/transmissão
9.
J Virol ; 95(20): e0066621, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34288734

RESUMO

Cedar virus (CedV) is a nonpathogenic member of the Henipavirus (HNV) genus of emerging viruses, which includes the deadly Nipah (NiV) and Hendra (HeV) viruses. CedV forms syncytia, a hallmark of henipaviral and paramyxoviral infections and pathogenicity. However, the intrinsic fusogenic capacity of CedV relative to NiV or HeV remains unquantified. HNV entry is mediated by concerted interactions between the attachment (G) and fusion (F) glycoproteins. Upon receptor binding by the HNV G head domain, a fusion-activating G stalk region is exposed and triggers F to undergo a conformational cascade that leads to viral entry or cell-cell fusion. Here, we demonstrate quantitatively that CedV is inherently significantly less fusogenic than NiV at equivalent G and F cell surface expression levels. We then generated and tested six headless CedV G mutants of distinct C-terminal stalk lengths, surprisingly revealing highly hyperfusogenic cell-cell fusion phenotypes 3- to 4-fold greater than wild-type CedV levels. Additionally, similarly to NiV, a headless HeV G mutant yielded a less pronounced hyperfusogenic phenotype compared to wild-type HeV. Further, coimmunoprecipitation and cell-cell fusion assays revealed heterotypic NiV/CedV functional G/F bidentate interactions, as well as evidence of HNV G head domain involvement beyond receptor binding or G stalk exposure. All evidence points to the G head/stalk junction being key to modulating HNV fusogenicity, supporting the notion that head domains play several distinct and central roles in modulating stalk domain fusion promotion. Further, this study exemplifies how CedV may help elucidate important mechanistic underpinnings of HNV entry and pathogenicity. IMPORTANCE The Henipavirus genus in the Paramyxoviridae family includes the zoonotic Nipah (NiV) and Hendra (HeV) viruses. NiV and HeV infections often cause fatal encephalitis and pneumonia, but no vaccines or therapeutics are currently approved for human use. Upon viral entry, Henipavirus infections yield the formation of multinucleated cells (syncytia). Viral entry and cell-cell fusion are mediated by the attachment (G) and fusion (F) glycoproteins. Cedar virus (CedV), a nonpathogenic henipavirus, may be a useful tool to gain knowledge on henipaviral pathogenicity. Here, using homotypic and heterotypic full-length and headless CedV, NiV, and HeV G/F combinations, we discovered that CedV G/F are significantly less fusogenic than NiV or HeV G/F, and that the G head/stalk junction is key to modulating cell-cell fusion, refining the mechanism of henipaviral membrane fusion events. Our study exemplifies how CedV may be a useful tool to elucidate broader mechanistic understanding for the important henipaviruses.


Assuntos
Henipavirus/metabolismo , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/metabolismo , Células Gigantes/metabolismo , Glicoproteínas/genética , Células HEK293 , Henipavirus/genética , Infecções por Henipavirus/metabolismo , Infecções por Henipavirus/virologia , Humanos , Fusão de Membrana/fisiologia , Receptores Virais/metabolismo , Proteínas do Envelope Viral/genética , Proteínas Virais de Fusão/fisiologia , Ligação Viral , Internalização do Vírus
10.
Antiviral Res ; 193: 105084, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34077807

RESUMO

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic, bat-borne paramyxoviruses in the genus Henipavirus that cause severe and often fatal acute respiratory and/or neurologic diseases in humans and livestock. There are currently no approved antiviral therapeutics or vaccines for use in humans to treat or prevent NiV or HeV infection. To facilitate development of henipavirus antivirals, a high-throughput screening (HTS) platform was developed based on a well-characterized recombinant version of the nonpathogenic Henipavirus, Cedar virus (rCedV). Using reverse genetics, a rCedV encoding firefly luciferase (rCedV-Luc) was rescued and its utility evaluated for high-throughput antiviral compound screening. The luciferase reporter gene signal kinetics of rCedV-Luc in different human cell lines was characterized and validated as an authentic real-time measure of viral growth. The rCedV-Luc platform was optimized as an HTS assay that demonstrated high sensitivity with robust Z' scores, excellent signal-to-background ratios and coefficients of variation. Eight candidate compounds that inhibited rCedV replication were identified for additional validation and demonstrated that 4 compounds inhibited authentic NiV-Bangladesh replication. Further evaluation of 2 of the 4 validated compounds in a 9-point dose response titration demonstrated potent antiviral activity against NiV-Bangladesh and HeV, with minimal cytotoxicity. This rCedV reporter can serve as a surrogate yet authentic BSL-2 henipavirus platform that will dramatically accelerate drug candidate identification in the development of anti-henipavirus therapies.


Assuntos
Antivirais/farmacologia , Infecções por Henipavirus/tratamento farmacológico , Henipavirus/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Proteínas do Envelope Viral/metabolismo , Linhagem Celular , Genes Reporter , Henipavirus/fisiologia , Infecções por Henipavirus/virologia , Humanos , Luciferases/genética , Luciferases/metabolismo , Recombinação Genética , Proteínas do Envelope Viral/genética , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
11.
Viruses ; 13(3)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809833

RESUMO

Mojiang virus (MojV) is the first henipavirus identified in a rodent and known only by sequence data, whereas all other henipaviruses have been isolated from bats (Hendra virus, Nipah virus, Cedar virus) or discovered by sequence data from material of bat origin (Ghana virus). Ephrin-B2 and -B3 are entry receptors for Hendra and Nipah viruses, but Cedar virus can utilize human ephrin-B1, -B2, -A2 and -A5 and mouse ephrin-A1. However, the entry receptor for MojV remains unknown, and its species tropism is not well characterized. Here, we utilized recombinant full-length and soluble forms of the MojV fusion (F) and attachment (G) glycoproteins in membrane fusion and receptor tropism studies. MojV F and G were functionally competent and mediated cell-cell fusion in primate and rattine cells, albeit with low levels and slow fusion kinetics. Although a relative instability of the pre-fusion conformation of a soluble form of MojV F was observed, MojV F displayed significantly greater fusion activity when heterotypically paired with Ghana virus G. An exhaustive investigation of A- and B-class ephrins indicated that none serve as a primary receptor for MojV. The MojV cell fusion phenotype is therefore likely the result of receptor restriction rather than functional defects in recombinant MojV F and G glycoproteins.


Assuntos
Glicoproteínas/metabolismo , Infecções por Henipavirus/virologia , Henipavirus/fisiologia , Proteínas do Envelope Viral/metabolismo , Células A549 , Animais , Células CHO , Chlorocebus aethiops , Cricetulus , Células HEK293 , Células HeLa , Humanos , Fusão de Membrana , Células Vero , Internalização do Vírus
12.
Viral Immunol ; 34(1): 27-40, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33021467

RESUMO

Henipaviruses are single-stranded RNA viruses that have recently emerged as zoonotic pathogens, capable of causing severe acute respiratory disease and encephalitis in humans. The prototypical henipaviruses, Hendra henipavirus and Nipah henipavirus, are a major health concern as they have high mortality rates and no currently approved human vaccine or drug therapy. Understanding the mechanisms of viral replication and pathogenicity is of critical importance for therapeutic developments. A novel target for such therapies is the Henipavirus Matrix (M) protein, a multifunctional protein that drives viral assembly and inhibits the innate immune response. These multifunctional attributes promote a complicated lifecycle: while viral replication occurs in the cytoplasm, M traffics to the nucleus, where it is ubiquitinated, for correct cellular targeting and virion packaging. In this study, we review the relationship between the structure and functions of M. In specific cases, the compatibility between structural accessibility and protein functionality is not always evident, and we highlight areas that require further investigation.


Assuntos
Henipavirus , Espaço Intracelular/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo , Animais , Henipavirus/química , Humanos , Espaço Intracelular/virologia
13.
Cell ; 183(6): 1536-1550.e17, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33306954

RESUMO

Hendra (HeV) and Nipah (NiV) viruses are emerging zoonotic pathogens in the Henipavirus genus causing outbreaks of disease with very high case fatality rates. Here, we report the first naturally occurring human monoclonal antibodies (mAbs) against HeV receptor binding protein (RBP). All isolated mAbs neutralized HeV, and some also neutralized NiV. Epitope binning experiments identified five major antigenic sites on HeV-RBP. Animal studies demonstrated that the most potent cross-reactive neutralizing mAbs, HENV-26 and HENV-32, protected ferrets in lethal models of infection with NiV Bangladesh 3 days after exposure. We solved the crystal structures of mAb HENV-26 in complex with both HeV-RBP and NiV-RBP and of mAb HENV-32 in complex with HeV-RBP. The studies reveal diverse sites of vulnerability on RBP recognized by potent human mAbs that inhibit virus by multiple mechanisms. These studies identify promising prophylactic antibodies and define protective epitopes that can be used in rational vaccine design.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vírus Hendra/imunologia , Henipavirus/imunologia , Testes de Neutralização , Vírus Nipah/imunologia , Receptores Virais/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/isolamento & purificação , Antígenos Virais/imunologia , Sítios de Ligação , Ligação Competitiva , Encéfalo/patologia , Quirópteros/virologia , Reações Cruzadas/imunologia , Cristalografia por Raios X , Efrina-B2/metabolismo , Feminino , Furões/virologia , Humanos , Interferometria , Fígado/patologia , Modelos Moleculares , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Receptores Virais/química , Receptores Virais/metabolismo
14.
mBio ; 11(4)2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636246

RESUMO

Humans are infected with paramyxoviruses of different genera early in life, which induce cytotoxic T cells that may recognize conserved epitopes. This raises the question of whether cross-reactive T cells induced by antecedent paramyxovirus infections provide partial protection against highly lethal zoonotic Nipah virus infections. By characterizing a measles virus-specific but paramyxovirus cross-reactive human T cell clone, we discovered a highly conserved HLA-B*1501-restricted T cell epitope in the fusion protein. Using peptides, tetramers, and single cell sorting, we isolated a parainfluenza virus-specific T cell clone from a healthy adult and showed that both clones cleared Nipah virus-infected cells. We identified multiple conserved hot spots in paramyxovirus proteomes that contain other potentially cross-reactive epitopes. Our data suggest that, depending on HLA haplotype and history of paramyxovirus exposures, humans may have cross-reactive T cells that provide protection against Nipah virus. The effect of preferential boosting of these cross-reactive epitopes needs to be further studied in light of paramyxovirus vaccination studies.IMPORTANCE Humans encounter multiple paramyxoviruses early in life. This study shows that infection with common paramyxoviruses can induce T cells cross-reactive with the highly pathogenic Nipah virus. This demonstrates that the combination of paramyxovirus infection history and HLA haplotype affects immunity to phylogenetically related zoonotic paramyxoviruses.


Assuntos
Reações Cruzadas , Henipavirus/imunologia , Infecções por Paramyxoviridae/imunologia , Paramyxovirinae/imunologia , Linfócitos T/imunologia , Adulto , Animais , Epitopos de Linfócito T/imunologia , Antígenos HLA/imunologia , Humanos , Masculino , Vírus do Sarampo/imunologia , Vírus Nipah/imunologia , Zoonoses/imunologia , Zoonoses/virologia
15.
Viruses ; 12(4)2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32340278

RESUMO

The genus Henipavirus (HNVs) includes two fatal viruses, namely Nipah virus (NiV) and Hendra virus (HeV). Since 1994, NiV and HeV have been endemic to the Asia-Pacific region and responsible for more than 600 cases of infections. Two emerging HNVs, Ghana virus (GhV) and Mojiang virus (MojV), are speculated to be associated with unrecognized human diseases in Africa and China, respectively. Despite many efforts to develop vaccines against henipaviral diseases, there is presently no licensed human vaccine. As HNVs are highly pathogenic and diverse, it is necessary to develop universal vaccines to prevent future outbreaks. The attachment enveloped glycoprotein (G protein) of HNVs mediates HNV attachment to the host cell's surface receptors. G proteins have been used as a protective antigen in many vaccine candidates for HNVs. We performed quantitative studies on the antibody responses elicited by the G proteins of NiV, HeV, GhV, and MojV. We found that the G proteins of NiV and HeV elicited only a limited cross-reactive antibody response. Further, there was no cross-protection between MojV, GhV, and highly pathogenic HNVs. We then constructed a bivalent vaccine where the G proteins of NiV and HeV were fused with the human IgG1 Fc domain. The immunogenicity of the bivalent vaccine was compared with that of monovalent vaccines. Our results revealed that the Fc-based bivalent vaccine elicited a potent antibody response against both NiV and HeV. We also constructed a tetravalent Fc heterodimer fusion protein that contains the G protein domains of four HNVs. Immunization with the tetravalent vaccine elicited broad antibody responses against NiV, HeV, GhV, and MojV in mice, indicating compatibility among the four antigens in the Fc-fusion protein. These data suggest that our novel bivalent and tetravalent Fc-fusion proteins may be efficient candidates to prevent HNV infection.


Assuntos
Anticorpos Amplamente Neutralizantes/imunologia , Infecções por Henipavirus/prevenção & controle , Henipavirus/genética , Henipavirus/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Animais , Anticorpos Antivirais/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Vírus Hendra/imunologia , Henipavirus/classificação , Camundongos , Testes de Neutralização , Vírus Nipah/imunologia , Filogenia , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia
17.
Lancet Infect Dis ; 20(4): 445-454, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027842

RESUMO

BACKGROUND: The monoclonal antibody m102.4 is a potent, fully human antibody that neutralises Hendra and Nipah viruses in vitro and in vivo. We aimed to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of m102.4 in healthy adults. METHODS: In this double-blind, placebo-controlled, single-centre, dose-escalation, phase 1 trial of m102.4, we randomly assigned healthy adults aged 18-50 years with a body-mass index of 18·0-35·0 kg/m2 to one of five cohorts. A sentinel pair for each cohort was randomly assigned to either m102.4 or placebo. The remaining participants in each cohort were randomly assigned (5:1) to receive m102.4 or placebo. Cohorts 1-4 received a single intravenous infusion of m102.4 at doses of 1 mg/kg (cohort 1), 3 mg/kg (cohort 2), 10 mg/kg (cohort 3), and 20 mg/kg (cohort 4), and were monitored for 113 days. Cohort 5 received two infusions of 20 mg/kg 72 h apart and were monitored for 123 days. The primary outcomes were safety and tolerability. Secondary outcomes were pharmacokinetics and immunogenicity. Analyses were completed according to protocol. The study was registered on the Australian New Zealand Clinical Trials Registry, ACTRN12615000395538. FINDINGS: Between March 27, 2015, and June 16, 2016, 40 (52%) of 77 healthy screened adults were enrolled in the study. Eight participants were assigned to each cohort (six received m102.4 and two received placebo). 86 treatment-emergent adverse events were reported, with similar rates between placebo and treatment groups. The most common treatment-related event was headache (12 [40%] of 30 participants in the combined m102.4 group, and three [30%] of ten participants in the pooled placebo group). No deaths or severe adverse events leading to study discontinuation occurred. Pharmacokinetics based on those receiving m102.4 (n=30) were linear, with a median half-life of 663·3 h (range 474·3-735·1) for cohort 1, 466·3 h (382·8-522·3) for cohort 2, 397·0 h (333·9-491·8) for cohort 3, and 466·7 h (351·0-889·6) for cohort 4. The elimination kinetics of those receiving repeated dosing (cohort 5) were similar to those of single-dose recipients (median elimination half-time 472·0 [385·6-592·0]). Anti-m102.4 antibodies were not detected at any time-point during the study. INTERPRETATION: Single and repeated dosing of m102.4 were well tolerated and safe, displayed linear pharmacokinetics, and showed no evidence of an immunogenic response. This study will inform future dosing regimens for m102.4 to achieve prolonged exposure for systemic efficacy to prevent and treat henipavirus infections. FUNDING: Queensland Department of Health, the National Health and Medical Research Council, and the National Hendra Virus Research Program.


Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Glicoproteínas/imunologia , Voluntários Saudáveis , Henipavirus/imunologia , Imunogenicidade da Vacina , Segurança , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Austrália , Método Duplo-Cego , Feminino , Cefaleia/etiologia , Humanos , Infusões Intravenosas , Masculino
18.
J Infect Dis ; 221(Suppl 4): S375-S382, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32034942

RESUMO

Bat-borne zoonotic pathogens belonging to the family Paramxyoviridae, including Nipah and Hendra viruses, and the family Filoviridae, including Ebola and Marburg viruses, can cause severe disease and high mortality rates on spillover into human populations. Surveillance efforts for henipaviruses and filoviruses have been largely restricted to the Old World; however, recent studies suggest a potentially broader distribution for henipaviruses and filoviruses than previously recognized. In the current study, we screened for henipaviruses and filoviruses in New World bats collected across 4 locations in Trinidad near the coast of Venezuela. Bat tissue samples were screened using previously established reverse-transcription polymerase chain reaction assays. Serum were screened using a multiplex immunoassay to detect antibodies reactive with the envelope glycoprotein of viruses in the genus Henipavirus and the family Filoviridae. Serum samples were also screened by means of enzyme-linked immunosorbent assay for antibodies reactive with Nipah G and F glycoproteins. Of 84 serum samples, 28 were reactive with ≥1 henipavirus glycoprotein by ≥1 serological method, and 6 serum samples were reactive against ≥1 filovirus glycoproteins. These data provide evidence of potential circulation of viruses related to the henipaviruses and filoviruses in New World bats.


Assuntos
Quirópteros/virologia , Infecções por Filoviridae/veterinária , Filoviridae , Infecções por Henipavirus/veterinária , Henipavirus , Animais , Quirópteros/sangue , Quirópteros/classificação , Infecções por Filoviridae/epidemiologia , Infecções por Filoviridae/virologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/virologia , Testes Sorológicos , Trinidad e Tobago/epidemiologia
19.
J Infect Dis ; 221(Suppl 4): S383-S388, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-31784761

RESUMO

Viruses in the genus Henipavirus encompass 2 highly pathogenic emerging zoonotic pathogens, Hendra virus (HeV) and Nipah virus (NiV). Despite the impact on human health, there is currently limited full-genome sequence information available for henipaviruses. This lack of full-length genomes hampers our ability to understand the molecular drivers of henipavirus emergence. Furthermore, rapidly deployable viral genome sequencing can be an integral part of outbreak response and epidemiological investigations to study transmission chains. In this study, we describe the development of a reverse-transcription, long-range polymerase chain reaction (LRPCR) assay for efficient genome amplification of NiV, HeV, and a related non-pathogenic henipavirus, Cedar virus (CedPV). We then demonstrated the utility of our method by amplifying partial viral genomes from 6 HeV-infected tissue samples from Syrian hamsters and 4 tissue samples from a NiV-infected African green monkey with viral loads as low as 52 genome copies/mg. We subsequently sequenced the amplified genomes on the portable Oxford Nanopore MinION platform and analyzed the data using a newly developed field-deployable bioinformatic pipeline. Our LRPCR assay allows amplification and sequencing of 2 or 4 amplicons in semi-nested reactions. Coupled with an easy-to-use bioinformatics pipeline, this method is particularly useful in the field during outbreaks in resource-poor environments.


Assuntos
Henipavirus/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reação em Cadeia da Polimerase/métodos , Genoma Viral , RNA Viral
20.
Life Sci Alliance ; 3(1)2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862858

RESUMO

The emergent zoonotic henipaviruses, Hendra, and Nipah are responsible for frequent and fatal disease outbreaks in domestic animals and humans. Specificity of henipavirus attachment glycoproteins (G) for highly species-conserved ephrin ligands underpins their broad host range and is associated with systemic and neurological disease pathologies. Here, we demonstrate that Cedar virus (CedV)-a related henipavirus that is ostensibly nonpathogenic-possesses an idiosyncratic entry receptor repertoire that includes the common henipaviral receptor, ephrin-B2, but, distinct from pathogenic henipaviruses, does not include ephrin-B3. Uniquely among known henipaviruses, CedV can use ephrin-B1 for cellular entry. Structural analyses of CedV-G reveal a key region of molecular specificity that directs ephrin-B1 utilization, while preserving a universal mode of ephrin-B2 recognition. The structural and functional insights presented uncover diversity within the known henipavirus receptor repertoire and suggest that only modest structural changes may be required to modulate receptor specificities within this group of lethal human pathogens.


Assuntos
Efrina-B1/metabolismo , Infecções por Henipavirus/metabolismo , Henipavirus/fisiologia , Proteínas Virais de Fusão/metabolismo , Internalização do Vírus , Animais , Quirópteros/virologia , Chlorocebus aethiops , Efrina-B1/genética , Efrina-B2/genética , Efrina-B2/metabolismo , Células HEK293 , Henipavirus/isolamento & purificação , Infecções por Henipavirus/virologia , Humanos , Ligantes , Ligação Proteica , Estrutura Secundária de Proteína , Receptores Virais/metabolismo , Transfecção , Células Vero
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