Surface glycoproteins of an African henipavirus induce syncytium formation in a cell line derived from an African fruit bat, Hypsignathus monstrosus
15 Dec 2013-Journal of Virology (American Society for Microbiology)-Vol. 87, Iss: 24, pp 13889-13891
TL;DR: Serological screening and detection of genomic RNA indicates that members of the genus Henipavirus are present not only in Southeast Asia but also in African fruit bats, and the M74 glycoproteins show functional similarities to glycoprotein of Nipah virus.
Abstract: Serological screening and detection of genomic RNA indicates that members of the genus Henipavirus are present not only in Southeast Asia but also in African fruit bats. We demonstrate that the surface glycoproteins F and G of an African henipavirus (M74) induce syncytium formation in a kidney cell line derived from an African fruit bat, Hypsignathus monstrosus. Despite a less broad cell tropism, the M74 glycoproteins show functional similarities to glycoproteins of Nipah virus.
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TL;DR: To determine the potential for HNV spillover events among humans in Africa, well-curated sets of bat and human serum samples from Cameroon are examined for Nipah virus (NiV) cross-neutralizing antibodies ( NiV-X-Nabs).
Abstract: Zoonotic transmission of lethal henipaviruses (HNVs) from their natural fruit bat reservoirs to humans has only been reported in Australia and South/Southeast Asia. However, a recent study discovered numerous HNV clades in African bat samples. To determine the potential for HNV spillover events among humans in Africa, here we examine well-curated sets of bat (Eidolon helvum, n = 44) and human (n = 497) serum samples from Cameroon for Nipah virus (NiV) cross-neutralizing antibodies (NiV-X-Nabs). Using a vesicular stomatitis virus (VSV)-based pseudoparticle seroneutralization assay, we detect NiV-X-Nabs in 48% and 3-4% of the bat and human samples, respectively. Seropositive human samples are found almost exclusively in individuals who reported butchering bats for bushmeat. Seropositive human sera also neutralize Hendra virus and Gh-M74a (an African HNV) pseudoparticles, as well as live NiV. Butchering bat meat and living in areas undergoing deforestation are the most significant risk factors associated with seropositivity. Evidence for HNV spillover events warrants increased surveillance efforts.
136 citations
05 Jul 2016
TL;DR: The roles of these glycoproteins in distinct steps of the membrane fusion process can offer insights into evolutionary relationships among Paramyxoviridae genera and offer future targets for prophylactic and therapeutic development.
Abstract: The family Paramyxoviridae includes many viruses that significantly affect human and animal health. An essential step in the paramyxovirus life cycle is viral entry into host cells, mediated by virus-cell membrane fusion. Upon viral entry, infection results in expression of the paramyxoviral glycoproteins on the infected cell surface. This can lead to cell-cell fusion (syncytia formation), often linked to pathogenesis. Thus membrane fusion is essential for both viral entry and cell-cell fusion and an attractive target for therapeutic development. While there are important differences between viral-cell and cell-cell membrane fusion, many aspects are conserved. The paramyxoviruses generally utilize two envelope glycoproteins to orchestrate membrane fusion. Here, we discuss the roles of these glycoproteins in distinct steps of the membrane fusion process. These findings can offer insights into evolutionary relationships among Paramyxoviridae genera and offer future targets for prophylactic and therapeutic development.
45 citations
TL;DR: The successful generation of the first bat bone marrow-derived immune cells paves the way to unlocking the immune mechanisms that confer host resilience to pathogens in bats.
Abstract: Bats carry and shed many emerging infectious disease agents including Ebola virus and SARS-like Coronaviruses, yet they rarely display clinical symptoms of infection. Bat epithelial or fibroblast cell lines were previously established to study the bat immune response against viral infection. However, the lack of professional immune cells such as dendritic cells (DC) and macrophages has greatly limited the significance of current investigations. Using Pteropus alecto (P. alecto) GM-CSF plus IL4, FLT3L and CSF-1, we successfully generated bat bone marrow-derived DC and macrophages. Cells with the phenotype, morphology and functional features of monocyte-derived DC, bona fide DC or macrophages were obtained in GM-CSF/IL4, FLT3L or CSF-1 cultures, respectively. The successful generation of the first bat bone marrow-derived immune cells paves the way to unlocking the immune mechanisms that confer host resilience to pathogens in bats.
30 citations
TL;DR: Current progress in understanding bat-virus interactions in bat cell line systems is highlighted and some of the challenges and limitations associated with cell lines are highlighted.
28 citations
TL;DR: A parallel approach is proposed for research on rodent- and Insectivore-borne hantaviruses, taking the generation of novel rodent and insectivore cell lines from wildlife species into account, which would be also valuable for studies on further rodent-borne viruses, such as orthopox- and arenavirus.
Abstract: Due to novel, improved and high-throughput detection methods, there is a plethora of newly identified viruses within the genus Hantavirus. Furthermore, reservoir host species are increasingly recognized besides representatives of the order Rodentia, now including members of the mammalian orders Soricomorpha/Eulipotyphla and Chiroptera. Despite the great interest created by emerging zoonotic viruses, there is still a gross lack of in vitro models, which reflect the exclusive host adaptation of most zoonotic viruses. The usually narrow host range and genetic diversity of hantaviruses make them an exciting candidate for studying virus-host interactions on a cellular level. To do so, well-characterized reservoir cell lines covering a wide range of bat, insectivore and rodent species are essential. Most currently available cell culture models display a heterologous virus-host relationship and are therefore only of limited value. Here, we review the recently established approaches to generate reservoir-derived cell culture models for the in vitro study of virus-host interactions. These successfully used model systems almost exclusively originate from bats and bat-borne viruses other than hantaviruses. Therefore we propose a parallel approach for research on rodent- and insectivore-borne hantaviruses, taking the generation of novel rodent and insectivore cell lines from wildlife species into account. These cell lines would be also valuable for studies on further rodent-borne viruses, such as orthopox- and arenaviruses.
26 citations
Cites background from "Surface glycoproteins of an African..."
...Surface glycoproteins of African henipaviruses could induce syncytium formation in a cell line derived from an African fruit bat, indicating a similar strategy of virus entry for both Asian and African henipaviruses, and providing a cell culture model for isolation of these emerging viruses [92]....
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References
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TL;DR: A morbillivirus has been isolated and added to an increasing list of emerging viral diseases, which induced syncytia that developed in the endothelium of blood vessels, particularly the lungs.
Abstract: A morbillivirus has been isolated and added to an increasing list of emerging viral diseases. This virus caused an outbreak of fatal respiratory disease in horses and humans. Genetic analyses show it to be only distantly related to the classic morbilliviruses rinderpest, measles, and canine distemper. When seen by electron microscopy, viruses had 10- and 18-nanometer surface projections that gave them a "double-fringed" appearance. The virus induced syncytia that developed in the endothelium of blood vessels, particularly the lungs.
696 citations
TL;DR: It is proposed that this Hendra-like virus was the cause of the outbreak of encephalitis among pig-farmers in Malaysia and Clinically and epidemiologically the infection is distinct from infection by the Hendra virus.
657 citations
TL;DR: Major discoveries include evidence of an origin of Hendra- and Nipah virus in Africa, identification of a bat virus conspecific with the human mumps virus, detection of close relatives of respiratory syncytial virus, mouse pneumonia- and canine distemper virus in bats, as well as direct evidence of Sendai virus in rodents.
Abstract: The large virus family Paramyxoviridae includes some of the most significant human and livestock viruses, such as measles-, distemper-, mumps-, parainfluenza-, Newcastle disease-, respiratory syncytial virus and metapneumoviruses. Here we identify an estimated 66 new paramyxoviruses in a worldwide sample of 119 bat and rodent species (9,278 individuals). Major discoveries include evidence of an origin of Hendra- and Nipah virus in Africa, identification of a bat virus conspecific with the human mumps virus, detection of close relatives of respiratory syncytial virus, mouse pneumonia- and canine distemper virus in bats, as well as direct evidence of Sendai virus in rodents. Phylogenetic reconstruction of host associations suggests a predominance of host switches from bats to other mammals and birds. Hypothesis tests in a maximum likelihood framework permit the phylogenetic placement of bats as tentative hosts at ancestral nodes to both the major Paramyxoviridae subfamilies (Paramyxovirinae and Pneumovirinae). Future attempts to predict the emergence of novel paramyxoviruses in humans and livestock will have to rely fundamentally on these data.
566 citations
"Surface glycoproteins of an African..." refers background or methods in this paper
...This cell line may also be helpful in the isolation of infectious henipaviruses from African fruit bats and maybe even from bats of other geographic regions, such as Central America, where henipaviruslike viral RNA sequences have been reported (10)....
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...frames of the fusion (F) and attachment (G) proteins of the African bat henipavirus Eid_hel/GH-M74a/GHA/2009 (M74) (10) were inserted into the expression plasmids pCAGGS (M74 F) or...
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TL;DR: In this article, the authors collected 324 bats from 14 species on peninsular Malaysia and demonstrated that neutralizing antibodies to Nipah virus were demonstrated in five species, suggesting widespread infection in bat populations in Malaysia.
Abstract: Nipah virus, family Paramyxoviridae, caused disease in pigs and humans in peninsular Malaysia in 1998-99. Because Nipah virus appears closely related to Hendra virus, wildlife surveillance focused primarily on pteropid bats (suborder Megachiroptera), a natural host of Hendra virus in Australia. We collected 324 bats from 14 species on peninsular Malaysia. Neutralizing antibodies to Nipah virus were demonstrated in five species, suggesting widespread infection in bat populations in peninsular Malaysia.
475 citations
"Surface glycoproteins of an African..." refers background in this paper
...Natural reservoir hosts for henipaviruses are flying foxes of the genus Pteropus (4, 5)....
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...A related virus, cedar virus (CedPV), causing no clinical disease in animal infections, has been isolated from Pteropus alecto in Australia (7)....
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...paviruses are flying foxes of the genus Pteropus (4, 5)....
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TL;DR: EphrinB2, the membrane-bound ligand for the EphB class of receptor tyrosine kinases (RTKs), specifically binds to the attachment (G) glycoprotein of NiV, and data show that ephrin B2 is a functional receptor for NiV.
Abstract: Nipah virus, first recognized in 1999, is an emerging disease that causes fatal encephalitis in humans. Its natural host is thought to be the fruit bat but it is also found in pigs and other animals. It could pose a serious threat to the pig-farming industry and there is recent evidence of human-to-human transmission. A crucial receptor that the virus relies on to infect human cells has now been identified, suggesting ways that the infection might be countered by vaccines or drugs. The virus's attachment protein binds to the ephrinB2 receptor. This receptor is critical for normal vascular developmental processes and is present in tissues targeted by Nipah virus. The enzyme EphB4 can block the entry of the virus into the cell. Nipah virus (NiV) is an emergent paramyxovirus that causes fatal encephalitis in up to 70 per cent of infected patients1, and there is evidence of human–to–human transmission2. Endothelial syncytia, comprised of multinucleated giant-endothelial cells, are frequently found in NiV infections, and are mediated by the fusion (F) and attachment (G) envelope glycoproteins. Identification of the receptor for this virus will shed light on the pathobiology of NiV infection, and spur the rational development of effective therapeutics. Here we report that ephrinB2, the membrane-bound ligand for the EphB class of receptor tyrosine kinases (RTKs)3, specifically binds to the attachment (G) glycoprotein of NiV. Soluble Fc-fusion proteins of ephrinB2, but not ephrinB1, effectively block NiV fusion and entry into permissive cell types. Moreover, transfection of ephrinB2 into non-permissive cells renders them permissive for NiV fusion and entry. EphrinB2 is expressed on endothelial cells and neurons3,4, which is consistent with the known cellular tropism for NiV5. Significantly, we find that NiV-envelope-mediated infection of microvascular endothelial cells and primary cortical rat neurons is inhibited by soluble ephrinB2, but not by the related ephrinB1 protein. Cumulatively, our data show that ephrinB2 is a functional receptor for NiV.
422 citations
"Surface glycoproteins of an African..." refers background in this paper
...Infection by NiV and HeV is initiated by an attachment process that involves the interaction of the viral G protein with the cell surface receptor, ephrin B2/B3 (15, 16)....
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