Structure and native functionality of the glycoproteins presented by zoonotic bornaviruses (360G-Wellcome-226997_Z_23_Z)

The family Bornaviridae within the order Mononegavirales comprises enveloped negative sense single-stranded RNA viruses that cause encephalopathies with an often-fatal outcome in mammals, birds, and reptiles. In recent years, bornaviruses have emerged as zoonotic pathogens and have caused human fatalities on multiple occasions. In the absence of curative treatment, there is an urgent requirement for anti-bornaviral therapeutic strategies. As the sole viral surface antigen, the bornavirus glycoprotein (BorV-G) is responsible for receptor recognition and membrane fusion, thus constitutes the primary determinant of cell, tissue, and host tropism. BorV-G is genetically distinct from other characterised viral fusogens encoded by related virus families (e.g., Rhabdoviridae, Filoviridae) and its detailed structural information is lacking. The proposed research aims to utilise an integrative approach to provide a holistic understanding of BorV-G architecture and functionality. X-ray crystallography and single-particle cryo-EM will be employed to study BorV-G assemblies. Characterisation of G-receptor and G-antibody interactions will define the molecular determinants of tropism and the minimal components required for immunogen design. Cryo-ET and subtomogram averaging of cell surface-displayed BorV-G will assess the native G architecture in the context of vaccine-derived BorV-G processing. This work will provide a molecular-level blueprint that may guide the development of anti-bornaviral prophylactics.