Lipoprotein receptors help maintain lipid homeostasis in the brain, and their co-option by viruses for cell entry may disrupt host metabolism. This project will profile lipid and metabolic changes during Venezuelan equine encephalitis virus and Sindbis virus infection of lung and brain organoids, identify the signalling nodes and metabolic products required for infection and pathology, and assess whether metabolic inhibitors and metabolites have antiviral or cell-protective effects.

Alphaviruses such as Venezuelan equine encephalitis virus and Sindbis virus can spread to the central nervous system, but how they use lipoprotein receptors for entry in different tissues is unclear. This project will map receptor expression in lung and CNS cell types by single-cell sequencing and imaging, define receptor roles in infection of complex organoids using CRISPR/Cas9 knockouts, and test whether receptor-blocking antibodies can inhibit neuro-infection.