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Thijs Kuiken - One of the best experts on this subject based on the ideXlab platform.
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novel avian origin influenza a h7n9 Virus attaches to epithelium in both upper and lower respiratory tract of humans
American Journal of Pathology, 2013Co-Authors: Debby Van Riel, Ron A M Fouchier, Lonneke M Leijten, Miranda De Graaf, Jurre Y Siegers, Kirsty R Short, Monique I J Spronken, Eefje J A Schrauwen, Albert D M E Osterhaus, Thijs KuikenAbstract:Influenza A Viruses from animal reservoirs have the capacity to adapt to humans and cause influenza pandemics. The occurrence of an influenza pandemic requires efficient Virus transmission among humans, which is associated with Virus Attachment to the upper respiratory tract. Pandemic severity depends on Virus ability to cause pneumonia, which is associated with Virus Attachment to the lower respiratory tract. Recently, a novel avian-origin H7N9 influenza A Virus with unknown pandemic potential emerged in humans. We determined the pattern of Attachment of two genetically engineered Viruses containing the hemagglutinin of either influenza Virus A/Shanghai/1/13 or A/Anhui/1/13 to formalin-fixed human respiratory tract tissues using histochemical analysis. Our results show that the emerging H7N9 Virus attached moderately or abundantly to both upper and lower respiratory tract, a pattern not seen before for avian influenza A Viruses. With the caveat that Virus Attachment is only the first step in the Virus replication cycle, these results suggest that the emerging H7N9 Virus has the potential both to transmit efficiently among humans and to cause severe pneumonia.
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The pattern of influenza Virus Attachment varies among wild bird species
PLoS ONE, 2011Co-Authors: Elsa Jourdain, Jonas Waldenström, Vincent J. Munster, Björn Olsen, Thijs Kuiken, Debby Van Riel, Patrik EllströmAbstract:The ability to attach to host cells is one of the main determinants of the host range of influenza A Viruses. By using Virus histochemistry, we investigate the pattern of Virus Attachment of both a human and an avian influenza Virus in colon and trachea sections from 12 wild bird species. We show that significant variations exist, even between closely related avian species, which suggests that the ability of wild birds to serve as hosts for influenza Viruses strongly varies among species. These results will prove valuable to assess the possibilities of interspecies transmission of influenza Viruses in natural environments and better understand the ecology of influenza.
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DOI: 10.1126/science.1125548Supporting online material H5N1 Virus Attachment to lower respiratory tract
2010Co-Authors: Debby Van Riel, Vincent J. Munster, Thijs Kuiken, Emmie De Wit, Guus F. Rimmelzwaan, Ron A. M, Ab D. M. E. Osterhaus, Figs S, Table SAbstract:Experimental design To determine the cell types to which H5N1 Virus binds in the lower respiratory tract of humans, we determined the Attachment pattern of a recent highly pathogenic H5N1 Virus isolate from Asia in human tissues. We determined whether Attachment occurred to epithelial cells of the trachea, bronchi, bronchioles, and alveoli. The binding pattern of this H5N1 Virus was also determined in mammals that are used for experimental influenza Virus infections. Tissues from the lower respiratory tract of cynomolgus macaque, domestic cat, ferret, and mouse were included. As a control for the validity of the method, we examined the Attachment of H5N1 Virus and a currently circulating human H3N2 Virus on human and avian tissues with known receptor identity. Viruses Influenza A Virus A/Vietnam/1194/04 (H5N1) was isolated from a fatal human case. The Virus was kindly provided by Dr. W. Lim, Queen Mary Hospital, Hong Kong and propagated once in Madin-Darby canine kidney (MDCK) cells. Influenza Virus A/Netherlands/213/03 (H3N2) is a recent human isolate grown on MDCK cells, and was kindly provided by the National influenza Center, The Netherlands
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Seasonal and Pandemic Human Influenza Viruses Attach Better to Human Upper Respiratory Tract Epithelium than Avian Influenza Viruses
The American journal of pathology, 2010Co-Authors: Debby Van Riel, Vincent J. Munster, Emmie De Wit, Guus F. Rimmelzwaan, Ron A M Fouchier, Lonneke M Leijten, Albert D M E Osterhaus, Michael A. Den Bakker, Salin Chutinimitkul, Thijs KuikenAbstract:Influenza Viruses vary markedly in their efficiency of human-to-human transmission. This variation has been speculated to be determined in part by the tropism of influenza Virus for the human upper respiratory tract. To study this tropism, we determined the pattern of Virus Attachment by Virus histochemistry of three human and three avian influenza Viruses in human nasal septum, conchae, nasopharynx, paranasal sinuses, and larynx. We found that the human influenza Viruses—two seasonal influenza Viruses and pandemic H1N1 Virus—attached abundantly to ciliated epithelial cells and goblet cells throughout the upper respiratory tract. In contrast, the avian influenza Viruses, including the highly pathogenic H5N1 Virus, attached only rarely to epithelial cells or goblet cells. Both human and avian Viruses attached occasionally to cells of the submucosal glands. The pattern of Virus Attachment was similar among the different sites of the human upper respiratory tract for each Virus tested. We conclude that influenza Viruses that are transmitted efficiently among humans attach abundantly to human upper respiratory tract, whereas inefficiently transmitted influenza Viruses attach rarely. These results suggest that the ability of an influenza Virus to attach to human upper respiratory tract is a critical factor for efficient transmission in the human population.
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h5n1 Virus Attachment to lower respiratory tract
Science, 2006Co-Authors: Debby Van Riel, Vincent J. Munster, Guus F. Rimmelzwaan, Ab D. M. E. Osterhaus, Ron A M Fouchier, Thijs KuikenAbstract:Highly pathogenic avian influenza Virus (H5N1) may cause severe lower respiratory tract (LRT) disease in humans. However, the LRT cells to which the Virus attaches are unknown for both humans and other mammals. We show here that H5N1 Virus attached predominantly to type II pneumocytes, alveolar macrophages, and nonciliated bronchiolar cells in the human LRT, and this pattern was most closely mirrored in cat and ferret tissues. These findings may explain, at least in part, the localization and severity of H5N1 viral pneumonia in humans. They also identify the cat and the ferret as suitable experimental animals based on this criterion.
Nathalie Ruvoenclouet - One of the best experts on this subject based on the ideXlab platform.
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a fut2 gene common polymorphism determines resistance to rotaVirus a of the p 8 genotype
The Journal of Infectious Diseases, 2014Co-Authors: Berthemarie Imbertmarcille, Laure Barbe, Mathilde Dupe, Beatrice Le Moullacvaidye, Bernard Besse, Cecile Peltier, Nathalie Ruvoenclouet, Jacques Le PenduAbstract:Attachment to carbohydrates of the histo-blood group type of several human RotaVirus strains (RVA) has recently been described. Synthesis of these ligands requires a functional FUT2 enzyme, suggesting that FUT2 null homozygote (ie, nonsecretor) individuals may not be recognized by most human RVA strains. Whereas such individuals represent 20% of the control population, this retrospective study determined that none of 51 patients infected by P[8] rotaVirus strains were nonsecretors. The lack of α1,2fucosylated carbohydrate motifs in the gut surface mucosa is thus associated with resistance to symptomatic infection and Virus Attachment to such motifs is essential to the infection process.
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influence of the combined abo fut2 and fut3 polymorphism on susceptibility to norwalk Virus Attachment
The Journal of Infectious Diseases, 2005Co-Authors: Severine Marionneau, Nathalie Ruvoenclouet, Jacques Le Pendu, Nicolai V Bovin, Fabrice AiraudAbstract:4 Shemyakin Institute of Bioorganic Chemistry, Moscow, Russia The binding of Norwalk Virus (NV) recombinant capsids was tested in a panel of saliva samples collected from 96 donors with different ABO, secretor, and Lewis phenotypes. As previously reported, binding occurred specifically to saliva from secretors, regardless of their Lewis phenotype status. Blood group B saliva was poorly recognized, whereas binding to blood group O saliva was higher and binding to blood group A saliva was highest. Transfection of either blood group A or B enzyme into H epitope-expressing cells showed that masking of H epitopes by the A and B antigens blocked the Attachment of NV capsids. The high level of binding to blood group A secretor saliva could be explained by an optimal H type 1 ligand density, which was lower than that in blood group O saliva and much higher than that in blood group B saliva. Indeed, despite a higher ligand density, saliva from homozygotes with 2 functional FUT2 alleles was less strongly recognized than saliva from heterozygotes with 1 functional and 1 inactivated FUT2 allele. Partial fucosidase treatment of duodenal tissue sections and binding to a synthetic probe with varying densities of H type 1 trisaccharide indicated that optimal Attachment occurred at medium ligand density.
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influence of the combined abo fut2 and fut3 polymorphism on susceptibility to norwalk Virus Attachment
The Journal of Infectious Diseases, 2005Co-Authors: Severine Marionneau, Nathalie Ruvoenclouet, Jacques Le Pendu, Nicolai V Bovin, Fabrice AiraudAbstract:The binding of Norwalk Virus (NV) recombinant capsids was tested in a panel of saliva samples collected from 96 donors with different ABO, secretor, and Lewis phenotypes. As previously reported, binding occurred specifically to saliva from secretors, regardless of their Lewis phenotype status. Blood group B saliva was poorly recognized, whereas binding to blood group O saliva was higher and binding to blood group A saliva was highest. Transfection of either blood group A or B enzyme into H epitope-expressing cells showed that masking of H epitopes by the A and B antigens blocked the Attachment of NV capsids. The high level of binding to blood group A secretor saliva could be explained by an optimal H type 1 ligand density, which was lower than that in blood group O saliva and much higher than that in blood group B saliva. Indeed, despite a higher ligand density, saliva from homozygotes with 2 functional FUT2 alleles was less strongly recognized than saliva from heterozygotes with 1 functional and 1 inactivated FUT2 allele. Partial fucosidase treatment of duodenal tissue sections and binding to a synthetic probe with varying densities of H type 1 trisaccharide indicated that optimal Attachment occurred at medium ligand density.
Debby Van Riel - One of the best experts on this subject based on the ideXlab platform.
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novel avian origin influenza a h7n9 Virus attaches to epithelium in both upper and lower respiratory tract of humans
American Journal of Pathology, 2013Co-Authors: Debby Van Riel, Ron A M Fouchier, Lonneke M Leijten, Miranda De Graaf, Jurre Y Siegers, Kirsty R Short, Monique I J Spronken, Eefje J A Schrauwen, Albert D M E Osterhaus, Thijs KuikenAbstract:Influenza A Viruses from animal reservoirs have the capacity to adapt to humans and cause influenza pandemics. The occurrence of an influenza pandemic requires efficient Virus transmission among humans, which is associated with Virus Attachment to the upper respiratory tract. Pandemic severity depends on Virus ability to cause pneumonia, which is associated with Virus Attachment to the lower respiratory tract. Recently, a novel avian-origin H7N9 influenza A Virus with unknown pandemic potential emerged in humans. We determined the pattern of Attachment of two genetically engineered Viruses containing the hemagglutinin of either influenza Virus A/Shanghai/1/13 or A/Anhui/1/13 to formalin-fixed human respiratory tract tissues using histochemical analysis. Our results show that the emerging H7N9 Virus attached moderately or abundantly to both upper and lower respiratory tract, a pattern not seen before for avian influenza A Viruses. With the caveat that Virus Attachment is only the first step in the Virus replication cycle, these results suggest that the emerging H7N9 Virus has the potential both to transmit efficiently among humans and to cause severe pneumonia.
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The pattern of influenza Virus Attachment varies among wild bird species
PLoS ONE, 2011Co-Authors: Elsa Jourdain, Jonas Waldenström, Vincent J. Munster, Björn Olsen, Thijs Kuiken, Debby Van Riel, Patrik EllströmAbstract:The ability to attach to host cells is one of the main determinants of the host range of influenza A Viruses. By using Virus histochemistry, we investigate the pattern of Virus Attachment of both a human and an avian influenza Virus in colon and trachea sections from 12 wild bird species. We show that significant variations exist, even between closely related avian species, which suggests that the ability of wild birds to serve as hosts for influenza Viruses strongly varies among species. These results will prove valuable to assess the possibilities of interspecies transmission of influenza Viruses in natural environments and better understand the ecology of influenza.
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DOI: 10.1126/science.1125548Supporting online material H5N1 Virus Attachment to lower respiratory tract
2010Co-Authors: Debby Van Riel, Vincent J. Munster, Thijs Kuiken, Emmie De Wit, Guus F. Rimmelzwaan, Ron A. M, Ab D. M. E. Osterhaus, Figs S, Table SAbstract:Experimental design To determine the cell types to which H5N1 Virus binds in the lower respiratory tract of humans, we determined the Attachment pattern of a recent highly pathogenic H5N1 Virus isolate from Asia in human tissues. We determined whether Attachment occurred to epithelial cells of the trachea, bronchi, bronchioles, and alveoli. The binding pattern of this H5N1 Virus was also determined in mammals that are used for experimental influenza Virus infections. Tissues from the lower respiratory tract of cynomolgus macaque, domestic cat, ferret, and mouse were included. As a control for the validity of the method, we examined the Attachment of H5N1 Virus and a currently circulating human H3N2 Virus on human and avian tissues with known receptor identity. Viruses Influenza A Virus A/Vietnam/1194/04 (H5N1) was isolated from a fatal human case. The Virus was kindly provided by Dr. W. Lim, Queen Mary Hospital, Hong Kong and propagated once in Madin-Darby canine kidney (MDCK) cells. Influenza Virus A/Netherlands/213/03 (H3N2) is a recent human isolate grown on MDCK cells, and was kindly provided by the National influenza Center, The Netherlands
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Seasonal and Pandemic Human Influenza Viruses Attach Better to Human Upper Respiratory Tract Epithelium than Avian Influenza Viruses
The American journal of pathology, 2010Co-Authors: Debby Van Riel, Vincent J. Munster, Emmie De Wit, Guus F. Rimmelzwaan, Ron A M Fouchier, Lonneke M Leijten, Albert D M E Osterhaus, Michael A. Den Bakker, Salin Chutinimitkul, Thijs KuikenAbstract:Influenza Viruses vary markedly in their efficiency of human-to-human transmission. This variation has been speculated to be determined in part by the tropism of influenza Virus for the human upper respiratory tract. To study this tropism, we determined the pattern of Virus Attachment by Virus histochemistry of three human and three avian influenza Viruses in human nasal septum, conchae, nasopharynx, paranasal sinuses, and larynx. We found that the human influenza Viruses—two seasonal influenza Viruses and pandemic H1N1 Virus—attached abundantly to ciliated epithelial cells and goblet cells throughout the upper respiratory tract. In contrast, the avian influenza Viruses, including the highly pathogenic H5N1 Virus, attached only rarely to epithelial cells or goblet cells. Both human and avian Viruses attached occasionally to cells of the submucosal glands. The pattern of Virus Attachment was similar among the different sites of the human upper respiratory tract for each Virus tested. We conclude that influenza Viruses that are transmitted efficiently among humans attach abundantly to human upper respiratory tract, whereas inefficiently transmitted influenza Viruses attach rarely. These results suggest that the ability of an influenza Virus to attach to human upper respiratory tract is a critical factor for efficient transmission in the human population.
Jeffrey M Bergelson - One of the best experts on this subject based on the ideXlab platform.
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the suramin derivative nf449 interacts with the 5 fold vertex of the enteroVirus a71 capsid to prevent Virus Attachment to psgl 1 and heparan sulfate
PLOS Pathogens, 2015Co-Authors: Susan Hafenstein, Jeffrey M Bergelson, Yorihiro Nishimura, Noel P Mclaughlin, Sara R Goldstein, Hiroyuki Shimizu, Jeffrey D WinklerAbstract:NF449, a sulfated compound derived from the antiparasitic drug suramin, was previously reported to inhibit infection by enteroVirus A71 (EV-A71). In the current work, we found that NF449 inhibits Virus Attachment to target cells, and specifically blocks Virus interaction with two identified receptors—the P-selectin ligand, PSGL-1, and heparan sulfate glycosaminoglycan—with no effect on Virus binding to a third receptor, the scavenger receptor SCARB2. We also examined a number of commercially available suramin analogues, and newly synthesized derivatives of NF449; among these, NF110 and NM16, like NF449, inhibited Virus Attachment at submicromolar concentrations. PSGL-1 and heparan sulfate, but not SCARB2, are both sulfated molecules, and their interaction with EV-A71 is thought to involve positively charged capsid residues, including a conserved lysine at VP1-244, near the icosahedral 5-fold vertex. We found that mutation of VP1-244 resulted in resistance to NF449, suggesting that this residue is involved in NF449 interaction with the Virus capsid. Consistent with this idea, NF449 and NF110 prevented Virus interaction with monoclonal antibody MA28-7, which specifically recognizes an epitope overlapping VP1-244 at the 5-fold vertex. Based on these observations we propose that NF449 and related compounds compete with sulfated receptor molecules for a binding site at the 5-fold vertex of the EV-A71 capsid.
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specificity of coxsackieVirus b3 interaction with human but not murine decay accelerating factor replacement of a single residue within short consensus repeat 2 prevents Virus Attachment
Journal of Virology, 2015Co-Authors: Lili Zhang, Lindsey J Organtini, Susan Hafenstein, Jeffrey M BergelsonAbstract:Many coxsackieVirus B (CVB) isolates bind to human decay-accelerating factor (DAF) as well as to the coxsackieVirus and adenoVirus receptor (CAR). However, the Virus does not interact with murine DAF. To understand why CVB3 binds specifically to human DAF, we constructed a series of chimeric molecules in which specific regions of the human DAF molecule were replaced by the corresponding murine sequences. We found that replacement of human short consensus repeat 2 (SCR2) with murine SCR2 ablated Virus binding to human DAF, as did deletion of human SCR2. Although replacement of human SCR4 had a partial inhibitory effect, deletion of SCR4 had no effect. Within human SCR2, replacement of serine 104 (S104) with the proline residue found in murine DAF eliminated Virus binding. On the basis of the structure of the CVB3-DAF complex determined by cryo-electron microscopy, DAF S104 is in close contact with a viral capsid residue, a threonine at VP1 position 271. Replacement of this capsid residue with larger amino acids specifically eliminated Virus Attachment to human DAF but had no effect on Attachment to CAR or replication in HeLa cells. Taken together, these results support the current model of Virus-DAF interaction and point to a specific role for VP1 T271 and DAF S104 at the Virus-DAF interface. IMPORTANCE The results of the present study point to a specific role for VP1 T271 and DAF S104 at the interface between CVB3 and DAF, and they demonstrate how subtle structural changes can dramatically influence Virus-receptor interactions. In addition, the results support a recent pseudoatomic model of the CVB3-DAF interaction obtained by cryo-electron microscopy.
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polioVirus entry into human brain microvascular cells requires receptor induced activation of shp 2
The EMBO Journal, 2007Co-Authors: Carolyn B Coyne, Jeffrey M Bergelson, Kwang Sik KimAbstract:Viruses use specific receptor molecules to bind selectively to target cells. Receptors have often been considered as mere docking sites, but they may also possess intrinsic signaling capacities that serve to prime the cell for entry and infection. PolioVirus (PV) initiates infection by binding to the PV receptor (PVR) and causes paralytic poliomyelitis by replicating within motor neurons of the brain and spinal cord. We have examined the process by which PV enters cultured human brain microvascular endothelial cells (HBMEC), an in vitro model of the blood–brain barrier. We found that PV enters HBMEC by dynamin-dependent caveolar endocytosis, and that entry depends on intracellular signals triggered by Virus Attachment to PVR. Tyrosine kinase and RhoA GTPase activation initiated by PVR ligation were both essential. Virus Attachment also induced tyrosine phosphorylation of PVR; this permitted the association of PVR with SHP-2, a protein tyrosine phosphatase whose activation was required for entry and infection. The results indicate that receptor-induced signals promote Virus entry and suggest a role for tyrosine phosphatases in viral pathogenesis.
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Virus induced abl and fyn kinase signals permit coxsackieVirus entry through epithelial tight junctions
Cell, 2006Co-Authors: Jeffrey M Bergelson, Carolyn B CoyneAbstract:Group B coxsackieViruses (CVBs) must cross the epithelium as they initiate infection, but the mechanism by which this occurs remains uncertain. The coxsackieVirus and adenoVirus receptor (CAR) is a component of the tight junction and is inaccessible to Virus approaching from the apical surface. Many CVBs also interact with the GPI-anchored protein decay-accelerating factor (DAF). Here, we report that Virus Attachment to DAF on the apical cell surface activates Abl kinase, triggering Rac-dependent actin rearrangements that permit Virus movement to the tight junction. Within the junction, interaction with CAR promotes conformational changes in the Virus capsid that are essential for Virus entry and release of viral RNA. Interaction with DAF also activates Fyn kinase, an event that is required for the phosphorylation of caveolin and transport of Virus into the cell within caveolar vesicles. CVBs thus exploit DAF-mediated signaling pathways to surmount the epithelial barrier.
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coxsackieVirus and adenoVirus receptor cytoplasmic and transmembrane domains are not essential for coxsackieVirus and adenoVirus infection
Journal of Virology, 1999Co-Authors: Xianghong Wang, Jeffrey M BergelsonAbstract:CoxsackieVirus and adenoVirus receptor (CAR) from which the cytoplasmic domain had been deleted and glycosylphosphatidylinositol (GPI)-anchored CAR lacking both transmembrane and cytoplasmic domains were both capable of facilitating adenoVirus 5-mediated gene delivery and infection by coxsackieVirus B3. These results indicate that the CAR extracellular domain is sufficient to permit Virus Attachment and entry and that the presence of a GPI anchor does not prevent infection.
Di Stuart - One of the best experts on this subject based on the ideXlab platform.
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seneca valley Virus Attachment and uncoating mediated by its receptor anthrax toxin receptor 1
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Rui Zhang, M Hu, Lingpeng Cheng, S Fu, J Hu, X H Li, Caiting Yu, H Wang, H Chen, Di StuartAbstract:Seneca Valley Virus (SVV) is an oncolytic picornaVirus with selective tropism for neuroendocrine cancers. SVV mediates cell entry by Attachment to the receptor anthrax toxin receptor 1 (ANTXR1). Here we determine atomic structures of mature SVV particles alone and in complex with ANTXR1 in both neutral and acidic conditions, as well as empty “spent” particles in complex with ANTXR1 in acidic conditions by cryoelectron microscopy. SVV engages ANTXR1 mainly by the VP2 DF and VP1 CD loops, leading to structural changes in the VP1 GH loop and VP3 GH loop, which attenuate interprotomer interactions and destabilize the capsid assembly. Despite lying on the edge of the Attachment site, VP2 D146 interacts with the metal ion in ANTXR1 and is required for cell entry. Though the individual substitution of most interacting residues abolishes receptor binding and Virus propagation, a serine-to-alanine mutation at VP2 S177 significantly increases SVV proliferation. Acidification of the SVV–ANTXR1 complex results in a major reconfiguration of the pentameric capsid assemblies, which rotate ∼20° around the icosahedral fivefold axes to form a previously uncharacterized spent particle resembling a potential uncoating intermediate with remarkable perforations at both two- and threefold axes. These structures provide high-resolution snapshots of SVV entry, highlighting opportunities for anticancer therapeutic optimization.
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Dimeric architecture of the Hendra Virus Attachment glycoprotein: evidence for a conserved mode of assembly
'American Society for Microbiology', 2010Co-Authors: Ta Bowden, E Y Jones, Crispin M, Dj Harvey, Di StuartAbstract:Hendra Virus is a negative-sense single-stranded RNA Virus within the Paramyxoviridae family which, together with Nipah Virus, forms the HenipaVirus genus. Infection with bat-borne Hendra Virus leads to a disease with high mortality rates in humans. We determined the crystal structure of the unliganded six-bladed beta-propeller domain and compared it to the previously reported structure of Hendra Virus Attachment glycoprotein (HeV-G) in complex with its cellular receptor, ephrin-B2. As observed for the related unliganded Nipah Virus structure, there is plasticity in the Glu579-Pro590 and Lys236-Ala245 ephrin-binding loops prior to receptor engagement. These data reveal that henipaviral Attachment glycoproteins undergo common structural transitions upon receptor binding and further define the structural template for antihenipaviral drug design. Our analysis also provides experimental evidence for a dimeric arrangement of HeV-G that exhibits striking similarity to those observed in crystal structures of related paramyxoVirus receptor-binding glycoproteins. The biological relevance of this dimer is further supported by the positional analysis of glycosylation sites from across the paramyxoViruses. In HeV-G, the sites lie away from the putative dimer interface and remain accessible to alpha-mannosidase processing on oligomerization. We therefore propose that the overall mode of dimer assembly is conserved for all paramyxoViruses; however, while the geometry of dimerization is rather closely similar for those Viruses that bind flexible glycan receptors, significant (up to 60 degrees ) and different reconfigurations of the subunit packing (associated with a significant decrease in the size of the dimer interface) have accompanied the independent switching to high-affinity protein receptor binding in Hendra and measles Viruses
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crystal structure and carbohydrate analysis of nipah Virus Attachment glycoprotein a template for antiviral and vaccine design
Journal of Virology, 2008Co-Authors: Thomas A. Bowden, Max Crispin, David J. Harvey, Jonathan M. Grimes, E Y Jones, A R Aricescu, Di StuartAbstract:Two members of the paramyxoVirus family, Nipah Virus (NiV) and Hendra Virus (HeV), are recent additions to a growing number of agents of emergent diseases which use bats as a natural host. Identification of ephrin-B2 and ephrin-B3 as cellular receptors for these Viruses has enabled the development of immunotherapeutic reagents which prevent Virus Attachment and subsequent fusion. Here we present the structural analysis of the protein and carbohydrate components of the unbound viral Attachment glycoprotein of NiV glycoprotein (NiV-G) at a 2.2-A resolution. Comparison with its ephrin-B2-bound form reveals that conformational changes within the envelope glycoprotein are required to achieve viral Attachment. Structural differences are particularly pronounced in the 579-590 loop, a major component of the ephrin binding surface. In addition, the 236-245 loop is rather disordered in the unbound structure. We extend our structural characterization of NiV-G with mass spectrometric analysis of the carbohydrate moieties. We demonstrate that NiV-G is largely devoid of the oligomannose-type glycans that in Viruses such as human immunodeficiency Virus type 1 and Ebola Virus influence viral tropism and the host immune response. Nevertheless, we find putative ligands for the endothelial cell lectin, LSECtin. Finally, by mapping structural conservation and glycosylation site positions from other members of the paramyxoVirus family, we suggest the molecular surface involved in oligomerization. These results suggest possible pathways of Virus-host interaction and strategies for the optimization of recombinant vaccines.
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structural basis of nipah and hendra Virus Attachment to their cell surface receptor ephrin b2
Nature Structural & Molecular Biology, 2008Co-Authors: Thomas A. Bowden, Jonathan M. Grimes, Radu A Aricescu, Robert J C Gilbert, Yvonne E Jones, Di StuartAbstract:Nipah and Hendra Viruses are emergent paramyxoViruses, causing disease characterized by rapid onset and high mortality rates, resulting in their classification as Biosafety Level 4 pathogens. Their Attachment glycoproteins are essential for the recognition of the cell-surface receptors ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3). Here we report crystal structures of both Nipah and Hendra Attachment glycoproteins in complex with human EFNB2. In contrast to previously solved paramyxoVirus Attachment complexes, which are mediated by sialic acid interactions, the Nipah and Hendra complexes are maintained by an extensive protein-protein interface, including a crucial phenylalanine side chain on EFNB2 that fits snugly into a hydrophobic pocket on the viral protein. By analogy with the development of antivirals against sialic acid binding Viruses, these results provide a structural template to target antiviral inhibition of protein-protein interactions.
