Unraveling the role played by lipid droplets in the antiviral innate immune defenses

• Applicant: Gabrielle Vieyres, Ph.D.
• Subject Area: Virology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531424650

The interferon system is a major branch of our innate immune defense against incoming pathogens and often determines the outcome of viral infections. It is organized in two signaling cascades: (i) interferon production in response to pathogen detection and (ii) interferon response initiated by the interferon receptor and switching the cell and its neighbours to a broad antiviral state. Both cascades are tightly compartmentalized and involve players spread on different cellular organelles or structures. Recent evidence indicate that lipid droplets play a yet underappreciated role in the innate immune defense. Thus, lipid droplets remodel their protein coat upon bacteria sensing to harbour anti-bacterial effectors. Lipid droplets also accumulate upon many viral infections and their amount correlates with the efficiency of the interferon production and response. In this proposal, we aim to unravel the role played by lipid droplets in antiviral innate immunity. Because they are the main source of energy and metabolic hub in the cell, but also because they are highly dynamic, well connected to other organelles and endowed with a plethora of functions, lipid droplets are an attractive target for viruses which hijack them to complete different steps of their replication cycle. For the same reasons, lipid droplets could be useful to support or regulate the host cell defense effort. We also hypothesize that host cells might have evolved to place sentinels or defense mechanisms such as viral restriction factors on this strategic organelle. We will employ complementary bioinformatical and experimental approaches to elucidate the role played by lipid droplets in the interferon system. By meta-analysis of published datasets we already identified a set of proteins associated with lipid droplet biology and innate immunity, including several known antiviral proteins. Experimentally, we will combine proteomics and lipidomics to determine changes in the lipid droplet protein coat or lipid content during innate immune signaling. We will integrate these diverse datasets to identify lipid droplet functions associated with innate immune defense. Last, we will select individual proteins or pathways and determine the relevance of their lipid droplet association as well as their precise antiviral mechanism and/or implication in the interferon system. Altogether, this project will shed light on the regulation of the innate antiviral program and identify new restriction mechanisms targeting viral interactions with the host lipid metabolism. Furthermore, our findings might help understand the highest infection risk in the case of dysregulated lipid droplet metabolism, e.g. in obesity, and highlight new therapeutic targets against viral infections.

• DFG Programme: Research Grants