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1.
BMC Infect Dis ; 21(1): 162, 2021 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-33563231

RESUMEN

BACKGROUND: In June 2019, Nipah virus (NiV) infection was detected in a 21-year-old male (index case) of Ernakulum, Kerala, India. This study was undertaken to determine if NiV was in circulation in Pteropus species (spp) in those areas where the index case had visit history in 1 month. METHODS: Specialized techniques were used to trap the Pteropus medius bats (random sampling) in the vicinity of the index case area. Throat and rectal swabs samples of 141 bats along with visceral organs of 92 bats were collected to detect the presence of NiV by real-time reverse transcriptase-polymerase chain reaction (qRTPCR). Serum samples of 52 bats were tested for anti-NiV Immunoglobulin (Ig) G antibodies by Enzyme-Linked Immunosorbent Assay (ELISA). The complete genome of NiV was sequenced by next-generation sequencing (NGS) from the tissues and swab samples of bats. RESULTS: One rectal swab sample and three bats visceral organs were found positive for the NiV. Interestingly, 20.68% (12/58) of Pteropus were positive for anti-NiV IgG antibodies. NiV sequences of 18,172; 17,200 and 15,100 nucleotide bps could be retrieved from three Pteropus bats. CONCLUSION: A distinct cluster of NiV sequences, with significant net-evolutionary nucleotide divergence, was obtained, suggesting the circulation of new genotype (I-India) in South India. NiV Positivity in Pteropus spp. of bats revealed that NiV is circulating in many districts of Kerala state, and active surveillance of NiV should be immediately set up to know the hotspot area for NiV infection.


Asunto(s)
Quirópteros/virología , Infecciones por Henipavirus/diagnóstico , Virus Nipah/genética , Animales , Anticuerpos Antivirales/sangre , Brotes de Enfermedades , Infecciones por Henipavirus/epidemiología , Infecciones por Henipavirus/veterinaria , Infecciones por Henipavirus/virología , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunoglobulina G/sangre , India/epidemiología , Virus Nipah/clasificación , Virus Nipah/inmunología , Filogenia , ARN Viral/química , ARN Viral/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Recto/virología
2.
Nat Commun ; 11(1): 3849, 2020 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-32737300

RESUMEN

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.


Asunto(s)
Anticuerpos Antivirales/biosíntesis , Resistencia a la Enfermedad/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Henipavirus/genética , Interacciones Huésped-Patógeno/genética , Sarcoma de Kaposi/genética , Adolescente , Adulto , Antígenos Virales/genética , Antígenos Virales/inmunología , Proteínas de la Cápside/genética , Proteínas de la Cápside/inmunología , Coinfección , Infecciones por Virus de Epstein-Barr/epidemiología , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Antígenos Nucleares del Virus de Epstein-Barr/genética , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , VIH/genética , VIH/inmunología , VIH/patogenicidad , Cadenas alfa de HLA-DQ/genética , Cadenas alfa de HLA-DQ/inmunología , Infecciones por Henipavirus/epidemiología , Infecciones por Henipavirus/inmunología , Infecciones por Henipavirus/virología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/patogenicidad , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/inmunología , Herpesvirus Humano 8/patogenicidad , Interacciones Huésped-Patógeno/inmunología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Población Rural , Sarcoma de Kaposi/epidemiología , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/virología , Uganda/epidemiología , Población Urbana
3.
Am J Trop Med Hyg ; 103(3): 1241-1246, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32588798

RESUMEN

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.


Asunto(s)
Brotes de Enfermedades , Infecciones por Henipavirus/epidemiología , Virus Nipah/aislamiento & purificación , Femenino , Grupos Focales , Infecciones por Henipavirus/virología , Humanos , India/epidemiología , Masculino , Investigación Cualitativa
4.
J Infect Dis ; 221(Supplement_4): S480-S492, 2020 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-32037447

RESUMEN

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.


Asunto(s)
Antivirales/farmacología , Infecciones por Henipavirus/tratamiento farmacológico , Virus Nipah/efectos de los fármacos , Lectinas de Plantas/farmacología , Internalización del Virus/efectos de los fármacos , Animales , Antivirales/uso terapéutico , Chlorocebus aethiops , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Células HEK293 , Células HeLa , Infecciones por Henipavirus/virología , Humanos , Mesocricetus , Virus Nipah/aislamiento & purificación , Lectinas de Plantas/uso terapéutico , Células Vero
5.
Sci Rep ; 10(1): 1477, 2020 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-32001794

RESUMEN

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.


Asunto(s)
G-Cuádruplex , Genoma Viral , Virus Nipah/genética , Acridinas/farmacología , Antivirales/farmacología , Biología Computacional , Secuencia Conservada , G-Cuádruplex/efectos de los fármacos , Infecciones por Henipavirus/virología , Humanos , Enlace de Hidrógeno , India , Ligandos , Virus Nipah/efectos de los fármacos , Virus Nipah/fisiología , Porfirinas/farmacología , Internalización del Virus , Replicación Viral
6.
Database (Oxford) ; 20202020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-32090261

RESUMEN

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/.


Asunto(s)
Bases de Datos Genéticas , Infecciones por Henipavirus , Virus Nipah , Animales , Antivirales , Epítopos/genética , Genoma Viral/genética , Infecciones por Henipavirus/tratamiento farmacológico , Infecciones por Henipavirus/virología , Humanos , Patología Molecular , Filogenia , ARN no Traducido/genética , ARN Viral/genética
7.
Transbound Emerg Dis ; 67(1): 121-132, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31408582

RESUMEN

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.


Asunto(s)
Adaptación Biológica , Quirópteros/virología , Brotes de Enfermedades , Infecciones por Henipavirus/virología , Virus Nipah/genética , Polimorfismo Genético , Animales , Bangladesh/epidemiología , Evolución Biológica , Biología Computacional , Geografía , Infecciones por Henipavirus/epidemiología , Infecciones por Henipavirus/transmisión , Especificidad del Huésped , Humanos , Malasia/epidemiología , Modelos Moleculares , Virus Nipah/aislamiento & purificación , Virus Nipah/patogenicidad , Virus Nipah/fisiología , Filogenia , Proteínas Virales/genética
8.
Sci Rep ; 9(1): 16710, 2019 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-31723221

RESUMEN

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.


Asunto(s)
Infecciones por Henipavirus/patología , Infecciones por Henipavirus/virología , Virus Nipah/fisiología , Fosfoproteínas/metabolismo , Factor de Transcripción STAT1/antagonistas & inhibidores , Proteínas Virales/metabolismo , Proteínas Estructurales Virales/metabolismo , Animales , Anticuerpos Neutralizantes/inmunología , Sitios de Unión , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Hurones , Infecciones por Henipavirus/metabolismo , Fosfoproteínas/genética , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Proteínas Virales/genética , Proteínas Estructurales Virales/genética
9.
Nat Struct Mol Biol ; 26(10): 980-987, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31570878

RESUMEN

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.


Asunto(s)
Anticuerpos Neutralizantes/farmacología , Antivirales/farmacología , Virus Hendra/efectos de los fármacos , Infecciones por Henipavirus/tratamiento farmacológico , Virus Nipah/efectos de los fármacos , Proteínas Virales de Fusión/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Células HEK293 , Virus Hendra/metabolismo , Infecciones por Henipavirus/metabolismo , Infecciones por Henipavirus/virología , Humanos , Modelos Moleculares , Virus Nipah/metabolismo , Proteínas Virales de Fusión/metabolismo , Internalización del Virus/efectos de los fármacos
10.
Proc Natl Acad Sci U S A ; 116(41): 20707-20715, 2019 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-31548390

RESUMEN

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.


Asunto(s)
Efrina-B1/metabolismo , Efrina-B2/metabolismo , Efrina-B3/metabolismo , Infecciones por Henipavirus/virología , Henipavirus/fisiología , Receptores Virales/metabolismo , Proteínas del Envoltorio Viral/química , Animales , Fusión Celular , Efrina-B1/genética , Efrina-B2/genética , Efrina-B3/genética , Infecciones por Henipavirus/genética , Infecciones por Henipavirus/metabolismo , Humanos , Ratones , Mutación , Unión Proteica , Conformación Proteica , Receptores Virales/genética , Especificidad de la Especie , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo , Internalización del Virus
11.
Philos Trans R Soc Lond B Biol Sci ; 374(1782): 20190021, 2019 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-31401962

RESUMEN

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'.


Asunto(s)
Quirópteros , Reservorios de Enfermedades/veterinaria , Infecciones por Henipavirus/veterinaria , Henipavirus/fisiología , Animales , Animales de Zoológico , Reservorios de Enfermedades/virología , Ghana/epidemiología , Infecciones por Henipavirus/epidemiología , Infecciones por Henipavirus/transmisión , Infecciones por Henipavirus/virología , Prevalencia , Estudios Seroepidemiológicos
12.
Sci Rep ; 9(1): 11171, 2019 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31371748

RESUMEN

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.


Asunto(s)
Virus Nipah/genética , Animales , Bangladesh , Brotes de Enfermedades , Infecciones por Henipavirus/transmisión , Infecciones por Henipavirus/virología , Humanos , Malasia , Mesocricetus/virología , ARN Polimerasa II , Genética Inversa
13.
JCI Insight ; 4(14)2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31341108

RESUMEN

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.


Asunto(s)
Encéfalo/virología , Enfermedades Transmisibles Emergentes/patología , Infecciones por Henipavirus/patología , Virus Nipah/aislamiento & purificación , Zoonosis/patología , Animales , Encéfalo/irrigación sanguínea , Encéfalo/patología , Chlorocebus aethiops , Enfermedad Crónica , Enfermedades Transmisibles Emergentes/mortalidad , Enfermedades Transmisibles Emergentes/virología , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Endotelio Vascular/virología , Infecciones por Henipavirus/mortalidad , Infecciones por Henipavirus/virología , Humanos , Masculino , Virus Nipah/patogenicidad , Recurrencia , Sobrevivientes , Zoonosis/mortalidad , Zoonosis/virología
14.
Sci Transl Med ; 11(494)2019 05 29.
Artículo en Inglés | MEDLINE | ID: mdl-31142680

RESUMEN

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.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Infecciones por Henipavirus/tratamiento farmacológico , Infecciones por Henipavirus/virología , Virus Nipah/efectos de los fármacos , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/farmacología , Alanina/uso terapéutico , Animales , Encéfalo/patología , Encéfalo/virología , Chlorocebus aethiops , Femenino , Infecciones por Henipavirus/sangre , Masculino , Meningoencefalitis/tratamiento farmacológico , Meningoencefalitis/virología , Pruebas de Neutralización , Viremia/sangre , Viremia/tratamiento farmacológico , Viremia/virología , Replicación Viral/efectos de los fármacos
15.
Emerg Infect Dis ; 25(6): 1144-1152, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31107231

RESUMEN

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.


Asunto(s)
Chlorocebus aethiops , Infecciones por Henipavirus/veterinaria , Virus Nipah , Vesiculovirus/inmunología , Vacunas Virales/inmunología , Zoonosis , Animales , Femenino , Infecciones por Henipavirus/mortalidad , Infecciones por Henipavirus/prevención & control , Infecciones por Henipavirus/virología , Humanos , Inmunidad Humoral , Masculino , Enfermedades de los Monos/patología , Enfermedades de los Monos/virología , Carga Viral
16.
J Virol ; 93(13)2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-30971473

RESUMEN

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.


Asunto(s)
Glicoproteínas/metabolismo , Virus Hendra/fisiología , Infecciones por Henipavirus/virología , Virus Nipah/fisiología , Fenotipo , Proteínas Virales de Fusión/fisiología , Células Gigantes/metabolismo , Glicoproteínas/genética , Células HEK293 , Virus Hendra/genética , Humanos , Fusión de Membrana , Virus Nipah/genética , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/fisiología , Proteínas Virales de Fusión/genética , Acoplamiento Viral , Internalización del Virus
17.
PLoS Pathog ; 15(4): e1007733, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-31034506

RESUMEN

Formation of cytoplasmic inclusion bodies (IBs) is a hallmark of infections with non-segmented negative-strand RNA viruses (order Mononegavirales). We show here that Nipah virus (NiV), a bat-derived highly pathogenic member of the Paramyxoviridae family, differs from mononegaviruses of the Rhabdo-, Filo- and Pneumoviridae families by forming two types of IBs with distinct localizations, formation kinetics, and protein compositions. IBs in the perinuclear region form rapidly upon expression of the nucleocapsid proteins. These IBperi are highly mobile and associate with the aggresome marker y-tubulin. IBperi can recruit unrelated overexpressed cytosolic proteins but do not contain the viral matrix (M) protein. Additionally, NiV forms an as yet undescribed IB population at the plasma membrane (IBPM) that is y-tubulin-negative but contains the M protein. Infection studies with recombinant NiV revealed that IBPM require the M protein for their formation, and most likely represent sites of NiV assembly and budding. The identification of this novel type of plasma membrane-associated IBs not only provides new insights into NiV biology and may open new avenues to develop novel antiviral approaches to treat these highly pathogenic viruses, it also provides a basis for a more detailed characterization of IBs and their role in virus assembly and replication in infections with other Mononegavirales.


Asunto(s)
Membrana Celular/virología , Infecciones por Henipavirus/virología , Cuerpos de Inclusión Viral/virología , Virus Nipah/patogenicidad , Proteínas de la Matriz Viral/metabolismo , Animales , Chlorocebus aethiops , Glicoproteínas/metabolismo , Infecciones por Henipavirus/metabolismo , Infecciones por Henipavirus/patología , Humanos , Cuerpos de Inclusión Viral/metabolismo , Cuerpos de Inclusión Viral/patología , Células Vero , Ensamble de Virus , Internalización del Virus
18.
Emerg Infect Dis ; 25(5): 1003-1006, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31002049

RESUMEN

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.


Asunto(s)
Quirópteros/virología , Brotes de Enfermedades , Infecciones por Henipavirus/epidemiología , Infecciones por Henipavirus/virología , Virus Nipah/clasificación , Virus Nipah/genética , Animales , Células Cultivadas , Efecto Citopatogénico Viral , Infecciones por Henipavirus/historia , Infecciones por Henipavirus/transmisión , Historia del Siglo XXI , Humanos , India/epidemiología , Mutación , Vigilancia en Salud Pública
20.
Vet Q ; 39(1): 26-55, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31006350

RESUMEN

Nipah (Nee-pa) viral disease is a zoonotic infection caused by Nipah virus (NiV), a paramyxovirus belonging to the genus Henipavirus of the family Paramyxoviridae. It is a biosafety level-4 pathogen, which is transmitted by specific types of fruit bats, mainly Pteropus spp. which are natural reservoir host. The disease was reported for the first time from the Kampung Sungai Nipah village of Malaysia in 1998. Human-to-human transmission also occurs. Outbreaks have been reported also from other countries in South and Southeast Asia. Phylogenetic analysis affirmed the circulation of two major clades of NiV as based on currently available complete N and G gene sequences. NiV isolates from Malaysia and Cambodia clustered together in NiV-MY clade, whereas isolates from Bangladesh and India clusterered within NiV-BD clade. NiV isolates from Thailand harboured mixed population of sequences. In humans, the virus is responsible for causing rapidly progressing severe illness which might be characterized by severe respiratory illness and/or deadly encephalitis. In pigs below six months of age, respiratory illness along with nervous symptoms may develop. Different types of enzyme-linked immunosorbent assays along with molecular methods based on polymerase chain reaction have been developed for diagnostic purposes. Due to the expensive nature of the antibody drugs, identification of broad-spectrum antivirals is essential along with focusing on small interfering RNAs (siRNAs). High pathogenicity of NiV in humans, and lack of vaccines or therapeutics to counter this disease have attracted attention of researchers worldwide for developing effective NiV vaccine and treatment regimens.


Asunto(s)
Infecciones por Henipavirus/veterinaria , Virus Nipah/inmunología , Vacunas Virales , Zoonosis , Animales , Enfermedades de los Gatos/epidemiología , Enfermedades de los Gatos/prevención & control , Enfermedades de los Gatos/virología , Gatos , Enfermedades de los Perros/epidemiología , Enfermedades de los Perros/prevención & control , Enfermedades de los Perros/virología , Perros , Infecciones por Henipavirus/epidemiología , Infecciones por Henipavirus/prevención & control , Infecciones por Henipavirus/virología , Humanos , Virus Nipah/clasificación , Vacunas Virales/administración & dosificación , Vacunas Virales/análisis , Vacunas Virales/uso terapéutico , Zoonosis/epidemiología , Zoonosis/prevención & control , Zoonosis/virología
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