Phagocytosis of filamentous fungi by macrophages

我研究的总体长期目标是了解控制细胞内病原体和宿主细胞之间相互作用的机制，包括巨噬细胞(M)。管家的作用包括清除病原体、异物颗粒和细胞碎片。这些作用依赖于吞噬作用，吞噬作用是M识别、内化和降解靶标的过程。吞噬作用的研究传统上是使用乳胶珠、酵母和红细胞作为标准靶标。这使得能够阐明控制吞噬作用的分子和细胞机制，并描绘了一条详细的途径。然而，这些“典型”靶点的均匀球状形态在很大程度上不能反映巨噬细胞面对的靶点的形态和尺寸的异质性。因此，靶细胞形态对巨噬细胞吞噬功能的影响知之甚少。这与丝状细胞形态的靶细胞特别相关，丝状细胞形态被认为是巨噬细胞吞噬的障碍。我的NSERC研究项目研究丝状靶形态对吞噬作用的影响。这项提案将重点放在霉菌菌丝的吞噬作用上。霉菌产生长长的多细胞细丝，称为菌丝。菌丝不能被M吞噬，因为它们的长度超过了这些细胞的吞噬能力。试图吞噬菌丝的M会缠绕在这个目标周围，并抓住丝状物。这种现象对霉菌降解的贡献是有争议的，它对M的影响也是未知的。我对这一提议的总体假设是，由于MS缺乏吞噬整个菌丝的能力，MS将从追求吞噬转变为支持形成专门的吞噬杯(PC)，该杯在进行细胞外降解的同时保持住靶标。这一建议的具体目的是：1)研究菌丝和菌丝之间建立的PC的形态发生和功能。2)研究巨噬细胞如何维持菌丝的长期吞噬作用。3)评价巨多核细胞在菌丝吞噬过程中的作用。NSERC程序对细胞生物学、先天免疫和膜转运领域具有重要意义。这将填补巨噬细胞生物学知识的一个重要空白，并将导致对巨噬细胞如何处理霉菌菌丝和其他非吞噬目标的更好理解。

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.