Interrogating the Native Functionality and Antibody-Mediated Immune Targeting of the Lassa Virus Glycoprotein Spike at a Molecular Level

Lassa virus (LASV) is an Old-World arenavirus endemic to West Africa and the causative agent of Lassa fever, a haemorrhagic disease with high morbidity and mortality. LASV entry and fusion with host cells are mediated by the glycoprotein complex (GP), a class I fusion protein displayed on the virion surface. GP is the primary target of neutralising antibodies following infection, thus a key focus for vaccine design efforts. This project seeks to define the structural basis of LASV entry and antibody-mediated immune recognition by characterising GP in its native membrane context. The specific aims are to: \- Determine the first high-resolution structure of full-length LASV GP embedded in virus-like particle membranes using cryo-electron microscopy. \- Elucidate the molecular interface between GP and the endosomal receptor LAMP1, defining how this interaction promotes fusion. \- Dissect LASV fusion by capturing GP intermediates during LAMP1 engagement and fusion by cryo-electron tomography and subtomogram averaging. \- Map epitopes of human neutralising antibodies directly onto in situ GP, establishing how immune responses target the viral surface. Together, these aims will deliver molecular-level insights into LASV GP native functionality and accessibility and positioning of epitope clusters on envelope-bound GP, providing a blueprint for structure-guided vaccine design.