Regulation of Phagocyte Immunity by Lipid Signals

Phagocytosis, the process by which relatively large particles are internalized into a membrane-bound compartment known as the phagosome, is paramount to both fighting infection and maintaining tissue homeostasis. Professional phagocytes routinely contend with a large assortment of targets, ranging from small pathogenic bacteria to large fungal networks. Non-professional and professional phagocytes also cooperate in the daunting yet critical task of clearing hundreds of billions of apoptotic cells on a daily basis. By promptly removing effete cells, phagocytes prevent secondary necrosis and the onset of autoimmunity, aid in tissue remodelling during wound healing, and orchestrate morphogenesis throughout development. To carry out these functions, phagocytes must be able to effectively find, engulf and dispose of their prey. In this dissertation, I focus on the phagocytic response from the conceptual stages of: 1) capture, 2) uptake and 3) degradation-all presented as self-contained chapters-while placing particular emphasis on the mechanisms by which glycerophospholipids and diacylglycerols regulate these processes. I provide evidence that phosphatidic acid, which is uniquely enriched in the plasmalemma of professional phagocytes, facilitates the continuous membrane ruffling that underlies the uptake of particulate and fluid-phase antigen. Similarly, I argue that phosphatidylinositol-3,4,5-trisphosphate biosynthesis signals actin remodelling during the uptake of large particles, thereby mediating the orderly progression of pseudopodia around large targets. I then discuss the role of diacylglycerol kinases in controlling deployment of the NADPH oxidase, thus fine-tuning the compromise between eliciting effective antimicrobial responses and preventing oxidative damage to the host. Notably, phosphoinositide signalling is often subverted by invading microorganisms in order to avoid phagocyte recognition. The final study in this thesis, also a self-contained chapter, describes a phosphoinositide-centric mechanism by which gliotoxin, an Aspergillus fumigatus mycotoxin, precludes macrophage immune defences.Ph.D