Immune-induction of lipid droplets in Drosophila larval hemocytes

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Lipid droplets (LDs) are cytoplasmic fat storage organelles with fundamental roles in lipid metabolism, energy homeostasis, and signal transduction. In many infectious diseases, they accumulate in immune cells and can positively or negatively affect the ability of the organism to respond to infection. Despite important advances, it is difficult to assess the relevance of immune-induced LDs for the organism as a whole. Drosophila models have a great track record for providing generally important insights into both innate immunity and LD biology. The proposed project takes advantage of Drosophila to study the intersection between these fields. When Drosophila larvae are infected with bacteria, their macrophage-like blood cells (hemocytes) rapidly accumulate LDs. This response can also be triggered by bacterial cell wall components and depends critically on proteins of the Imd pathway, in particular the NF-kB transcription factor Relish. It is a very rapid response, with LD accumulation detectable within 40 minutes of stimulation. The deep conservation of other aspects of innate immunity and LD biology between flies and mammals suggests that this response could be broadly important. However, because a mechanistic understanding is lacking, it is currently impossible to test the biological significance of the response. This project will employ a two-pronged approach to uncover the underlying mechanisms of immune-induced LD formation. We will determine in which tissues/cells NF-kB/Relish functions to drive LD formation, with a tissue-specific RNAi approach. The role of other components of the Imd pathway will also be tested as well as whether the response relies on the known function of Relish as a transcriptional activator. To determine how the hemocyte LDs form, various pathways involved in LD biogenesis and turnover will be manipulated experimentally and the consequences for LD accumulation examined, both in the basal state and after immune induction. These studies will generate the tools and intellectual framework to test mechanistic hypotheses about the functional role of immune-induced hemocyte LDs and will illuminate macrophage lipid metabolism in general.