Structure-guided mutagenesis of Henipavirus receptor-binding proteins reveals molecular determinants of receptor usage and antibody-binding epitopes

Kasopefoluwa Y. Oguntuyo, Griffin D. Haas, Kristopher D. Azarm, Christian S. Stevens, Luca Brambilla, Shreyas S. Kowdle, Victoria A. Avanzato, Rhys Pryce, Alexander N. Freiberg, Thomas A. Bowden, Benhur Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Nipah virus (NiV) is a highly lethal, zoonotic Henipavirus (HNV) that causes respiratory and neurological signs and symptoms in humans.Similar to other paramyxoviruses, HNVs mediate entry into host cells through the concerted actions of two surface glycoproteins: a receptor-binding protein (RBP) that mediates attachment and a fusion glycoprotein (F) that triggers fusion in an RBP-dependent manner.NiV uses ephrin-B2 (EFNB2) and ephrin-B3 (EFNB3) as entry receptors.Ghana virus (GhV), a novel HNV identified in a Ghanaian bat, uses EFNB2 but not EFNB3.In this study, we employ a structure-informed approach to identify receptor-interfacing residues and systematically introduce GhV-RBP residues into a NiV-RBP backbone to uncover the molecular determinants of EFNB3 usage.We reveal two regions that severely impair EFNB3 binding by NiV-RBP and EFNB3-mediated entry by NiV pseudotyped viral particles.Further analyses uncovered two-point mutations (NiVN557SGhV and NiVY581TGhV) pivotal for this phenotype.Moreover, we identify NiV interaction with Y120 of EFNB3 as important for the usage of this receptor.Beyond these EFNB3-related findings, we reveal two domains that restrict GhV binding of EFNB2, confirm the HNV-head as an immunodominant target for polyclonal and monoclonal antibodies, and describe putative epitopes for GhV- and NiV-specific monoclonal antibodies.Cumulatively, the work presented here generates useful reagents and tools that shed insight to residues important for NiV usage of EFNB3, reveal regions critical for GhV binding of EFNB2, and describe putative HNV antibody-binding epitopes.

Original languageEnglish (US)
JournalJournal of virology
Volume98
Issue number3
DOIs
StatePublished - Mar 2024
Externally publishedYes

Keywords

  • antibody
  • EFNB2/EFNB3
  • Ghana virus
  • Hendra virus
  • Henipavirus
  • molecular biology
  • Nipah virus
  • receptor-binding protein
  • structural biology
  • virus entry

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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