Phagocytosis of filamentous fungi by macrophages

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The overall long-term objective of my research is to understand the mechanisms that govern the interactions between intracellular pathogens and host-cells, including Macrophages (M). M housekeeping roles include elimination of pathogens, foreign particles and cellular debris. These roles depend on phagocytosis, a process by which M recognize, internalize and degrade targets. Phagocytosis has been traditionally studied using latex beads, yeast and erythrocytes as standard targets. This enabled elucidation of the molecular and cellular mechanisms that control phagocytosis and delineation of a detailed pathway. However, the uniform spheroidal morphology of these “canonical” targets largely underrepresent the morphological and dimensional heterogeneity of the targets that macrophages face. Consequently, little is known about how target morphology affects phagocytosis in macrophages.This is of special relevance for targets of filamentous morphology, that has been considered a hurdle for phagocytosis. ***My NSERC research program studies the effect of filamentous target morphology on phagocytosis. This proposal will focus on the phagocytosis of hyphae from molds. Molds produce long multicellular filaments known as hyphae. Hyphae cannot be engulfed by M because they are longer than the swallowing capacity of these cells. A M attempting to engulf a hypha will wrap around this target and keep hold of the filament. The contribution of this phenomenon to the degradation of molds is controversial, and its effect on M is unknown. My overall hypothesis for this proposal is that since Ms lack the capacity to ingest a whole hypha, Ms will shift from pursuing phagocytosis to favouring the formation of a specialized phagocytic cup (PC), which keeps hold on the target while it carries out its extracellular degradation. ***The specific aims for this proposal are:***1) Study the morphogenesis and functionality of the PC established between hyphae and M. ***2) Investigate how macrophages sustain the long-lasting phagocytosis of hyphae. ***3) Assess the role of Giant Multi Nucleated Cells in the phagocytosis of hyphae.***This NSERC program will be of great interest to the cell biology, innate immunity and membrane trafficking fields. This will fill an important gap in the knowledge of macrophage biology and will lead to a better understanding of how macrophages deal with mold hyphae and other non-phagocytable targets. *****