Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Our immune system is composed of various cell types that create a network to defend our body against pathogens. An example of these immune cells are the macrophages that recognize and internalize a plethora of viruses, bacteria and fungi through phagocytosis. The internalized pathogen is sequestered in a new organelle called the phagosome, which then fuses with acidic and hydrolytic organelles called lysosomes by a process known as phagosome maturation. This fusion is necessary for the degradation of phagosomal content such as bacteria by lysosomal enzymes. Different types of proteins and lipids are involved and regulate the process of phagosome maturation. For example, phosphoinositides are signalling lipids that help control phagosome maturation. Recently, I found that one of these phosphoinositides, phosphatidylinositol-3,5-bisphosphate (PI3,5P2), is important for phagosome maturation. Inhibition of PI(3,5)P2 synthesis causes enlargement of lysosomes, decreases their degradation capability, and impaired with the fusion of phagosomes with lysosomes. I am now trying to determine how PI(3,5)P2 in is important for phagosome maturation by identifying PI(3,5)P2 effectors necessary for this. In particular, I am investigating the role of TRPML1, a calcium channel found on lysosomes and that allows release of Ca2+ from lysosomes into the cytosol to stimulate lysosome fusion. The activity of TRPML1 is controlled by PI(3,5)P2. Our preliminary data suggest that loss of TRPML1 impairs fusion of phagosomes with lysosomes, which can be rescued by artificial release of Ca2+ with drugs. Overall, I am currently investigating the relationship between PI(3,5)P2, TRPML and Ca+2 in phagosome maturation and pathogen killing.