FOR 5815 " Structural and functional lipid droplet heterogeneity", Project: Interplay between hepatitis C virus and the hepatic lipid droplet mosaic

Hepatitis C virus is a liver-tropic pathogen that chronically infects around 71 million people worldwide. Its replication cycle is tightly entangled with the host cell lipid metabolism. In particular, the virus targets two of its ten viral proteins, the capsid protein and the non-structural protein 5A, to the surface of the host lipid droplets and hijacks this organelle for virion morphogenesis. Lipid droplets are the main energy reservoir of the cell but also accomplish a plethora of other functions. This complexity is reflected by their specific proteome and the co-existence of distinct lipid droplet subsets between cells but also within single cells. Our preliminary results indicate that during infection, hepatitis C virus does not hijack to the same extent all lipid droplets within the cell. We therefore aim to understand the relevance of lipid droplet heterogeneity in hepatitis C virus infection. To do so, we will assess lipid droplet subsets in naïve and virus-infected liver-derived cells. We will characterize the physical and biochemical properties of the droplets that are hijacked or not by the viral proteins, using high-resolution imaging and mass spectrometry for protein and lipid profiling. Finally, based on this differential analysis, we will identify host factors and pathways segregating on specific lipid droplet subsets and relevant to HCV replication or pathogenesis. While HCV is the most studied and possibly the most intricate example of a virus depending on lipid droplet metabolism, this host-pathogen interaction is conserved across various virus families including flaviviruses and picornaviruses. We therefore anticipate broader implications of our findings in the field of virology but also in the cell biology of lipid droplets where hepatitis C virus is a unique tool to dissect the complexity of the cell organization.