Entry and Antibody-Mediated Immune Targeting of Zoonotic Arenaviruses

Context and challenges:
Emerging zoonotic viruses can cross the species barrier from animals to humans and constitute a persistent and growing threat to global health. Among these, rodent-borne New World arenaviruses (NWAVs), which are endemic to South America, have been designated by the World Health Organization as ‘Priority Pathogens’ due to their ability to cause severe viral haemorrhagic fever (HF) with human case fatality rates reaching up to 25%. Although a live-attenuated vaccine for one NWAV, Junín virus (JUNV), has been made available to at-risk communities in Argentina (Candid-1), there are no internationally approved therapeutics for preventing or treating NWAV HF.
The NWAV envelope-displayed glycoprotein complex (GP) is presented on the virus surface and facilitates entry of the virion into host-cells. The ability of the GP to interact with the human host-cell surface receptor, transferrin receptor 1 (hTfR1) during host-cell entry is a primary determinant of zoonosis. Despite the importance of this host-cell recognition event, the molecular determinants underlying GP recognition of both native and human TfR1 for genetically diverse HF-causing NW GP1s remain undefined. Further, while the NWAV GP is the target for neutralising antibodies, information about the epitopes that can be targeted to achieve virus neutralisation and protection following vaccination and infection remains limited. Such information is essential for guiding efforts to rationally design immunogens that protect (and cross-protect) against NWAV infection and would provide a fundamental template for evaluating and improving vaccine designs.
Aims:
Our Project has two primary Aims.
Aim-1. We will engineer a recombinant NWAV GP ectodomain trimer exhibiting native-like functional and immunological properties. We will further combine high-resolution structural methods with biophysical and cellular assays to dissect the molecular specificity underlying TfR1-mediated entry of NW...