Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins
ABSTRACT A novel Hendra virus (HeV) genotype (HeV genotype 2 [HeV-g2]) was recently isolated from a deceased horse, revealing high-sequence conservation and antigenic similarities with the prototypic strain, HeV-g1. As the receptor-binding (G) and fusion (F) glycoproteins of HeV are essential for me...
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American Society for Microbiology
2025-02-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03482-23 |
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| author | Andrew Z. Ma Yao Yu Yeo Jean F. Lee Colin M. Kim Shahrzad Ezzatpour Carolina Menchaca Viraj Upadhye Edward J. Annand John-Sebastian Eden Raina K. Plowright Alison J. Peel David W. Buchholz Hector C. Aguilar |
| author_facet | Andrew Z. Ma Yao Yu Yeo Jean F. Lee Colin M. Kim Shahrzad Ezzatpour Carolina Menchaca Viraj Upadhye Edward J. Annand John-Sebastian Eden Raina K. Plowright Alison J. Peel David W. Buchholz Hector C. Aguilar |
| author_sort | Andrew Z. Ma |
| collection | DOAJ |
| description | ABSTRACT A novel Hendra virus (HeV) genotype (HeV genotype 2 [HeV-g2]) was recently isolated from a deceased horse, revealing high-sequence conservation and antigenic similarities with the prototypic strain, HeV-g1. As the receptor-binding (G) and fusion (F) glycoproteins of HeV are essential for mediating viral entry, functional characterization of emerging HeV genotypic variants is key to understanding viral entry mechanisms and broader virus-host co-evolution. We first confirmed that HeV-g2 and HeV-g1 glycoproteins share a close phylogenetic relationship, underscoring HeV-g2’s relevance to global health. Our in vitro data showed that HeV-g2 glycoproteins induced cell-cell fusion in human cells, shared receptor tropism with HeV-g1, and cross-reacted with antibodies raised against HeV-g1. Despite these similarities, HeV-g2 glycoproteins yielded reduced syncytia formation compared to HeV-g1. By expressing heterotypic combinations of HeV-g2, HeV-g1, and Nipah virus (NiV) glycoproteins, we found that while HeV-g2 G had strong fusion-promoting abilities, HeV-g2 F consistently displayed hypofusogenic properties. These fusion phenotypes were more closely associated with those observed in the related NiV. Further investigation using HeV-g1 and HeV-g2 glycoprotein chimeras revealed that multiple domains may play roles in modulating these fusion phenotypes. Altogether, our findings may establish intrinsic fusogenic capacities of viral glycoproteins as a potential driver behind the emergence of new henipaviral variants.IMPORTANCEHeV is a zoonotic pathogen that causes severe disease across various mammalian hosts, including horses and humans. The identification of unrecognized HeV variants, such as HeV-g2, highlights the need to investigate mechanisms that may drive their evolution, transmission, and pathogenicity. Our study reveals that HeV-g2 and HeV-g1 glycoproteins are highly conserved in identity, function, and receptor tropism, yet they differ in their abilities to induce the formation of multinucleated cells (syncytia), which is a potential marker of viral pathogenesis. By using heterotypic combinations of HeV-g2 with either HeV-g1 or NiV glycoproteins, as well as chimeric HeV-g1/HeV-g2 glycoproteins, we demonstrate that the differences in syncytial formation can be attributed to the intrinsic fusogenic capacities of each glycoprotein. Our data indicate that HeV-g2 glycoproteins have fusion phenotypes closely related to those of NiV and that fusion promotion may be a crucial factor driving the emergence of new henipaviral variants. |
| format | Article |
| id | doaj-art-47a57b75872c4a87888677e2ad9d0fa4 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | American Society for Microbiology |
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| series | mBio |
| spelling | doaj-art-47a57b75872c4a87888677e2ad9d0fa42025-02-05T14:00:48ZengAmerican Society for MicrobiologymBio2150-75112025-02-0116210.1128/mbio.03482-23Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteinsAndrew Z. Ma0Yao Yu Yeo1Jean F. Lee2Colin M. Kim3Shahrzad Ezzatpour4Carolina Menchaca5Viraj Upadhye6Edward J. Annand7John-Sebastian Eden8Raina K. Plowright9Alison J. Peel10David W. Buchholz11Hector C. Aguilar12Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USADepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USADepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USADepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USADepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USADepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USADepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USAEpidemiology Surveillance and Laboratory Section, Animal Health Policy Branch, Animal Division, Department of Agriculture Fisheries and Forestry, Canberra, Australian Capital Territory, AustraliaWestmead Institute for Medical Research, Centre for Virus Research, Westmead, New South Wales, AustraliaDepartment of Public and Ecosystem Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USACentre for Planetary Health and Food Security, School of Environment and Science, Griffith University, Nathan, Queensland, AustraliaDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USADepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USAABSTRACT A novel Hendra virus (HeV) genotype (HeV genotype 2 [HeV-g2]) was recently isolated from a deceased horse, revealing high-sequence conservation and antigenic similarities with the prototypic strain, HeV-g1. As the receptor-binding (G) and fusion (F) glycoproteins of HeV are essential for mediating viral entry, functional characterization of emerging HeV genotypic variants is key to understanding viral entry mechanisms and broader virus-host co-evolution. We first confirmed that HeV-g2 and HeV-g1 glycoproteins share a close phylogenetic relationship, underscoring HeV-g2’s relevance to global health. Our in vitro data showed that HeV-g2 glycoproteins induced cell-cell fusion in human cells, shared receptor tropism with HeV-g1, and cross-reacted with antibodies raised against HeV-g1. Despite these similarities, HeV-g2 glycoproteins yielded reduced syncytia formation compared to HeV-g1. By expressing heterotypic combinations of HeV-g2, HeV-g1, and Nipah virus (NiV) glycoproteins, we found that while HeV-g2 G had strong fusion-promoting abilities, HeV-g2 F consistently displayed hypofusogenic properties. These fusion phenotypes were more closely associated with those observed in the related NiV. Further investigation using HeV-g1 and HeV-g2 glycoprotein chimeras revealed that multiple domains may play roles in modulating these fusion phenotypes. Altogether, our findings may establish intrinsic fusogenic capacities of viral glycoproteins as a potential driver behind the emergence of new henipaviral variants.IMPORTANCEHeV is a zoonotic pathogen that causes severe disease across various mammalian hosts, including horses and humans. The identification of unrecognized HeV variants, such as HeV-g2, highlights the need to investigate mechanisms that may drive their evolution, transmission, and pathogenicity. Our study reveals that HeV-g2 and HeV-g1 glycoproteins are highly conserved in identity, function, and receptor tropism, yet they differ in their abilities to induce the formation of multinucleated cells (syncytia), which is a potential marker of viral pathogenesis. By using heterotypic combinations of HeV-g2 with either HeV-g1 or NiV glycoproteins, as well as chimeric HeV-g1/HeV-g2 glycoproteins, we demonstrate that the differences in syncytial formation can be attributed to the intrinsic fusogenic capacities of each glycoprotein. Our data indicate that HeV-g2 glycoproteins have fusion phenotypes closely related to those of NiV and that fusion promotion may be a crucial factor driving the emergence of new henipaviral variants.https://journals.asm.org/doi/10.1128/mbio.03482-23Hendra virusreceptor-binding proteinfusion proteinreceptorsyncytiaHenipavirus |
| spellingShingle | Andrew Z. Ma Yao Yu Yeo Jean F. Lee Colin M. Kim Shahrzad Ezzatpour Carolina Menchaca Viraj Upadhye Edward J. Annand John-Sebastian Eden Raina K. Plowright Alison J. Peel David W. Buchholz Hector C. Aguilar Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins mBio Hendra virus receptor-binding protein fusion protein receptor syncytia Henipavirus |
| title | Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins |
| title_full | Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins |
| title_fullStr | Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins |
| title_full_unstemmed | Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins |
| title_short | Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins |
| title_sort | functional assessment of the glycoproteins of a novel hendra virus variant reveals contrasting fusogenic capacities of the receptor binding and fusion glycoproteins |
| topic | Hendra virus receptor-binding protein fusion protein receptor syncytia Henipavirus |
| url | https://journals.asm.org/doi/10.1128/mbio.03482-23 |
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