Phagocytosis of filamentous fungi by macrophages

巨噬细胞对丝状真菌的吞噬作用

• 批准号: RGPIN-2018-05734
• 负责人: Terebiznik, Mauricio
• 金额: $ 4.23万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=666660
• 关键词: Phagocytosis; filamentous; fungi; macrophages

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 (MΦ). MΦ housekeeping roles include elimination of pathogens, foreign particles and cellular debris. These roles depend on phagocytosis, a process by which MΦ 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 MΦ because they are longer than the swallowing capacity of these cells. A MΦ 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 MΦ is unknown. My overall hypothesis for this proposal is that since MΦs lack the capacity to ingest a whole hypha, MΦs 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 MΦ. ***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. *****

我的研究的总体长期目标是了解胞内病原体和宿主细胞（包括巨噬细胞（MΦ））之间相互作用的机制。MΦ管家作用包括消除病原体、外来颗粒和细胞碎片。这些作用依赖于吞噬作用，这是MΦ识别、内化和降解靶标的过程。吞噬作用传统上使用乳胶珠、酵母和红细胞作为标准靶标进行研究。这使得能够阐明控制吞噬作用的分子和细胞机制并描绘详细的途径。然而，这些“典型”靶标的均匀球形形态在很大程度上低估了巨噬细胞所面临的靶标的形态和尺寸异质性。因此，很少有人知道靶形态如何影响巨噬细胞的吞噬作用。这是特别相关的丝状形态的目标，已被认为是吞噬作用的障碍。* 我的NSERC研究计划研究丝状靶形态对吞噬作用的影响。该提案将重点关注霉菌菌丝的吞噬作用。霉菌产生长的多细胞丝状物，称为菌丝。菌丝不能被MΦ吞噬，因为它们比这些细胞的吞噬能力长。一个试图吞噬菌丝的MΦ会包裹住这个目标并抓住菌丝。这种现象对霉菌降解的贡献是有争议的，其对MΦ的影响是未知的。我对这一提议的总体假设是，由于MΦ缺乏摄取整个菌丝的能力，MΦ将从追求吞噬作用转变为有利于形成专门的吞噬杯（PC），其在进行细胞外降解的同时保持目标。*** 本提案的具体目的是：***1）研究菌丝与MΦ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持久吞噬作用。*3）评估巨多核细胞在菌丝吞噬作用中的作用。*该NSERC计划将对细胞生物学，先天免疫和膜运输领域产生极大的兴趣。这将填补巨噬细胞生物学知识的一个重要空白，并将导致更好地了解巨噬细胞如何处理霉菌菌丝和其他非吞噬目标。*****