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: $ 8.45万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744907
• 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 (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.

我的研究的总体长期目标是了解控制细胞内病原体与宿主细胞（包括巨噬细胞（M））之间相互作用的机制。 M家政作用包括消除病原体，异物和细胞碎片。这些角色取决于吞噬作用，M识别，内部化和降解靶标的过程。传统上，吞噬作用是使用乳胶珠，酵母和红细胞作为标准靶标的研究。这有助于阐明控制吞噬作用和详细途径描述的分子和细胞机制。但是，这些“规范”靶标的均匀的球形形态在很大程度上不足以占巨噬细胞所面临的靶标的形态和维异质性。因此，靶向形态如何影响巨噬细胞中的吞噬作用知之甚少。这与丝状形态靶标具有特殊相关性，这被认为是吞噬作用的障碍。我的NSERC研究计划研究了丝状靶形态对吞噬作用的影响。该提案将集中于霉菌对菌丝的吞噬作用。霉菌产生长长的多细胞丝，称为菌丝。菌丝不能被M吞没，因为它们比这些细胞的吞咽能力更长。试图吞噬菌丝的m会围绕着这个目标，并保持灯丝。这种现象对模具降解的贡献是有争议的，其对M的影响尚不清楚。我对该提案的总体假设是，由于MS缺乏摄入整个菌丝的能力，因此MS将从追求吞噬作用转变为偏爱专门的吞噬杯（PC）的形成，该吞噬杯（PC）在靶向范围内保持其外细胞外降解。该提案的具体目的是：1）研究菌丝和M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）评估巨型多核细胞在菌丝吞噬作用中的作用。该NSERC计划将引起细胞生物学，先天免疫和膜贩运领域的极大兴趣。这将填补巨噬细胞知识的重要空白，并可以更好地理解巨噬细胞如何处理霉菌和其他不可变细胞的靶标。