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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 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 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. Objective: HeV 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.
Publication Date: 2024-12-20 PubMed ID: 39704501PubMed Central: PMC11796360DOI: 10.1128/mbio.03482-23Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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Overview
- This study analyzed the functional differences between the glycoproteins of a newly identified Hendra virus variant (HeV-g2) and the original strain (HeV-g1), focusing on how their fusion proteins contribute to viral entry and cell-cell fusion.
- Although HeV-g2 shares high genetic and antigenic similarity with HeV-g1, it exhibits distinct fusion behavior, which may influence viral infectivity and pathogenicity.
Background and Importance
- Hendra virus (HeV) is a zoonotic pathogen known to cause severe respiratory and neurological disease in horses and humans.
- The entry of HeV into host cells is mediated by two key glycoproteins on the viral surface:
- Glycoprotein G (receptor-binding protein)
- Glycoprotein F (fusion protein)
- Understanding the function of these glycoproteins is critical for insights into how the virus infects host cells and spreads, as well as for developing therapeutic or preventive strategies.
- Recently, a novel genotype of HeV, named HeV genotype 2 (HeV-g2), was isolated, raising questions about its functional and pathogenic properties compared to the prototypic HeV strain (HeV-g1).
Research Goals
- To compare the glycoproteins of HeV-g2 with those of HeV-g1, specifically regarding their phylogenetic relationship, receptor binding, and capacity to induce cell fusion.
- To explore how differences in the glycoproteins’ fusion abilities might influence viral pathogenicity and evolution.
- To use chimeric and heterotypic glycoprotein combinations from HeV-g1, HeV-g2, and a related virus, Nipah virus (NiV), to dissect the functional roles of each glycoprotein.
Key Findings
- Phylogenetic and Antigenic Relationships:
- HeV-g2 glycoproteins are closely related to HeV-g1, indicating they share a recent common ancestor and thus are relevant in global health contexts.
- Antibodies raised against HeV-g1 also recognize HeV-g2 glycoproteins, demonstrating antigenic similarity.
- Receptor Tropism and Fusion Capacity:
- Both HeV-g2 and HeV-g1 glycoproteins bind the same host cell receptor, indicating similar cell targeting.
- HeV-g2 glycoproteins induce fusion between cells (syncytia formation), but to a lesser extent than HeV-g1, indicating reduced fusogenicity.
- Heterotypic Glycoprotein Combinations:
- When mixing glycoproteins from HeV-g2, HeV-g1, and NiV, it was found that the HeV-g2 G protein strongly promotes fusion.
- The HeV-g2 F protein consistently showed lower fusion capacity (“hypofusogenic”) compared to HeV-g1 F.
- These fusion traits in HeV-g2 F resembled those of the related NiV F protein, linking HeV-g2 functionally closer to NiV in terms of fusion behavior.
- Chimeric Glycoprotein Studies:
- Creating hybrids (chimeras) between HeV-g1 and HeV-g2 glycoproteins showed that multiple structural domains contribute to their different fusion properties.
- This suggests that complex interactions within and between glycoprotein domains regulate viral fusion capacity.
Implications and Conclusions
- The intrinsic fusogenic properties of viral glycoproteins, especially the fusion (F) protein, play a significant role in virus-host interaction, viral spread, and potentially pathogenicity.
- The finding that HeV-g2 fusion characteristics are similar to Nipah virus indicates evolutionary and functional links among henipaviruses that could affect viral emergence and host adaptation.
- Reduced syncytia formation by HeV-g2 might influence the virus’s pathogenicity or transmissibility compared to HeV-g1, though more research would be needed to confirm clinical impacts.
- Understanding these functional differences provides key insights for surveillance of emerging variants and may inform the development of vaccines or therapeutics targeting viral entry mechanisms.
Cite This Article
APA
Ma AZ, Yeo YY, Lee JF, Kim CM, Ezzatpour S, Menchaca C, Upadhye V, Annand EJ, Eden J-S, Plowright RK, Peel AJ, Buchholz DW, Aguilar HC.
(2024).
Functional assessment of the glycoproteins of a novel Hendra virus variant reveals contrasting fusogenic capacities of the receptor-binding and fusion glycoproteins.
mBio, 16(2), e0348223.
https://doi.org/10.1128/mbio.03482-23 Publication
Researcher Affiliations
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Epidemiology Surveillance and Laboratory Section, Animal Health Policy Branch, Animal Division, Department of Agriculture Fisheries and Forestry, Canberra, Australian Capital Territory, Australia.
- Westmead Institute for Medical Research, Centre for Virus Research, Westmead, New South Wales, Australia.
- Department of Public and Ecosystem Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Centre for Planetary Health and Food Security, School of Environment and Science, Griffith University, Nathan, Queensland, Australia.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
MeSH Terms
- Hendra Virus / genetics
- Hendra Virus / physiology
- Hendra Virus / classification
- Animals
- Humans
- Horses
- Viral Fusion Proteins / genetics
- Viral Fusion Proteins / metabolism
- Virus Internalization
- Glycoproteins / genetics
- Glycoproteins / metabolism
- Receptors, Virus / metabolism
- Phylogeny
- Henipavirus Infections / virology
- Henipavirus Infections / veterinary
- Viral Tropism
- Genotype
- Cell Line
- Cell Fusion
- Viral Envelope Proteins / genetics
- Viral Envelope Proteins / metabolism
Grant Funding
- R01 AI109022 / NIAID NIH HHS
- T32 EB023860 / NIBIB NIH HHS
- D18AC00031-PREEMPT / DARPA
- DE190100710 / ARC DECRA
Conflict of Interest Statement
The authors declare no conflict of interest.
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