Uncovering mechanisms of phagocytosis by class A scavenger receptors

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Phagocytosis is an evolutionarily conserved process that likely originated to facilitate nutrient uptake in single-celled organisms and subsequently became essential to host-defence and homeostasis in multi-cellular organisms. The macrophage class A scavenger receptors are non-opsonic phagocytic receptors that recognize a number of natural (e.g. bacteria, modified lipoproteins) and synthetic ligands. Like other non-opsonic phagocytic receptors, they have no conventional signalling motifs in their cytoplasmic domains and yet transmit a phenomenal amount of information upon ligand recognition and uptake. We hypothesize that that the scavenger receptors contain previously uncharacterized motifs that contribute to phagocytosis and pro-inflammatory signalling, testable by these objectives;1) Discover functional domains in the scavenger receptors using ancient and modern genetics.2) Discover the role of lipid composition and transient lipid phases in scavenger receptor uptake. 3) Understand how cellular localization affects scavenger receptor signalling. Attempts to use traditional biochemical techniques to discover novel signalling motifs have provided insights into residues required for uptake, but have not been as fruitful as similar studies in opsonic receptors. We have shown (PMID:23181696) that a phylogenetic approach to discover evolutionarily conserved and divergent areas within these receptors provides a rich and robust method of attributing function to specific sequences and will expand and refine this approach in (Obj 1) by including studies of ancient (pre-mammalian) and modern (primates "> We have recently discovered that the scavenger receptors may depend more heavily on interactions with membrane lipids to initiate phagocytosis than the opsonic receptors (e.g. Fc receptors). We will elucidate these lipid interactions using high resolution microscopy to track scavenger receptor mobility in membranes (Obj 2). We have also determined that scavenger receptors collaborate with other innate immune receptors (i.e. the toll like receptors) but that their contribution to signalling is fundamentally different based on whether they are localized to the plasma membrane or the endosomal membrane. We have developed a number of molecular biology and cellular biology assays to dissect this interaction (Obj 3) and believe that this may be a heretofore undescribed mechanism of "fine-tuning" physiological responses to bacteria. The long-term goal of my research program is to understand the signalling processes of the non-opsonic phagocytic receptors. Since phagocytic receptors are essential for nutrient acquisition, host defence and multi-cellularity in lower organisms, and homeostasis and host defence in higher organisms, understanding the signalling capacity of these receptors will contribute to many biological questions.