Ma Andrew Z, Yeo Yao Yu, Lee Jean F, Kim Colin M, Ezzatpour Shahrzad, Menchaca Carolina, Upadhye Viraj, Annand Edward J, Eden John-Sebastian, Plowright Raina K, Peel Alison J, Buchholz David W, Aguilar Hector C
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.
mBio. 2025 Feb 5;16(2):e0348223. doi: 10.1128/mbio.03482-23. Epub 2024 Dec 20.
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.
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.
最近从一匹死亡的马身上分离出一种新型亨德拉病毒（HeV）基因型（HeV基因型2 [HeV - g2]），该基因型与原型毒株HeV - g1具有高度的序列保守性和抗原相似性。由于HeV的受体结合（G）糖蛋白和融合（F）糖蛋白对于介导病毒进入至关重要，因此对新出现的HeV基因型变体进行功能表征是理解病毒进入机制和更广泛的病毒 - 宿主共同进化的关键。我们首先证实HeV - g2和HeV - g1糖蛋白具有密切的系统发育关系，强调了HeV - g2与全球健康的相关性。我们的数据表明，HeV - g2糖蛋白在人类细胞中诱导细胞 - 细胞融合，与HeV - g1具有共同的受体嗜性，并且与针对HeV - g1产生的抗体发生交叉反应。尽管存在这些相似性，但与HeV - g1相比，HeV - g2糖蛋白产生的多核细胞形成（合胞体）减少。通过表达HeV - g2、HeV - g1和尼帕病毒（NiV）糖蛋白的异型组合，我们发现虽然HeV - g2 G具有强大的融合促进能力，但HeV - g2 F始终表现出低融合特性。这些融合表型与在相关NiV中观察到的表型更密切相关。使用HeV - g1和HeV - g2糖蛋白嵌合体的进一步研究表明，多个结构域可能在调节这些融合表型中发挥作用。总之，我们的发现可能将病毒糖蛋白的内在融合能力确立为新的亨尼帕病毒变体出现背后的潜在驱动因素。
HeV是一种人畜共患病原体，可以在包括马和人类在内的各种哺乳动物宿主中引起严重疾病。未被识别的HeV变体（如HeV - g2）的鉴定突出了研究可能驱动其进化、传播和致病性的机制的必要性。我们的研究表明，HeV - g2和HeV - g1糖蛋白在身份、功能和受体嗜性方面高度保守，但它们在诱导多核细胞（合胞体）形成的能力上有所不同，合胞体形成是病毒发病机制的一个潜在标志。通过使用HeV - g2与HeV - g1或NiV糖蛋白的异型组合以及嵌合的HeV - g1 / HeV - g2糖蛋白，我们证明合胞体形成的差异可归因于每种糖蛋白的内在融合能力。我们的数据表明，HeV - g2糖蛋白具有与NiV密切相关的融合表型，并且融合促进可能是驱动新的亨尼帕病毒变体出现的关键因素。
