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.
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We thank M. Whitt for permission to use the VSV-pseudotype system, B. Reversade for discussions, and K. Adams for editorial comments. This work was supported by NIH grants to B.L., an NIH NRSA grant to O.A.N., an emerging infectious disease training grant to A.B.-C., and a biodefence research fellowship to E.L.L. S.T. was supported by an NSF-funded UCLA-IGERT bioinformatics traineeship. B.L. is a recipient of the Burroughs Wellcome Fund Career Development Award and is also a Charles E. Culpepper Medical Scholar supported by the Rockefeller Brothers Fund and by Goldman Philanthropic Partnerships. We also acknowledge support from the UCLA AIDS Institute and the flow cytometry core (UCLA CFAR). Author Contributions E.L.L., H.C.A., A.B.-C. and R.N. contributed equally to this work.
This figure contains the protein sequence of EphrinB2; highlighting the two peptide fragments that were identified by LC-MS/MS (tandem MS).
Table I contains a list of deletions made in NiV-G that lead to the identification of δ28 NiV-G-Fc.
The methods used for the construction, production and measurement of NiV-G-Fc and sNiV-G-HA are outlined here.
About this article
Nature Medicine (2012)