溶酶体疾病通过破坏巨细胞迁移导致结核病的易感性
Russell D Berg1, Steven Levitte2, Mary P O'Sullivan3
1Molecular & Cellular Biology Graduate Program and Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.
Cell
|March 26, 2016
概括
一项对斑马鱼的研究显示,巨细胞的溶解体储存会损害细胞碎片的清除和对菌根的免疫反应. 这一发现提供了有关结核病易感性的见解,
科学领域:
- 免疫学
- 细胞生物学
- 遗传学
背景情况:
- 溶酶体储存疾病 (LSD) 是一种遗传性疾病,其特征在于溶酶体内积聚未消化的物质.
- 巨细胞在免疫反应中起着至关重要的作用,包括清除细胞碎片和病原体.
- 由Mycobacterium tuberculosis引起的结核病 (TB) 仍然是一个主要的全球健康问题,在某些人群中 (如吸烟者) 发现了更高的易感性.
研究的目的:
- 确定影响斑马鱼易受Mycobacterium marinum感染的遗传因素.
- 在斑马鱼的溶酶体储存模型中研究底层的细胞机制.
- 探索这些发现对人类结核病易感性的相关性,特别是在吸烟者中.
主要方法:
- 在斑马鱼中进行前置基因查,以识别对Mycobacterium marinum敏感度增加的突变物.
- 使用实时成像和显微镜对变异斑马鱼的巨溶酶功能和迁移进行表征.
- 对吸烟者的膜巨细胞进行分析,以检测溶解体积累和迁移缺陷.
主要成果:
- 一种斑马鱼突变体缺乏 lysosomal cysteine cathepsins 显示了 lysosomal 储存,破坏了内细胞循环,并影响了巨细胞的迁移.
- 受感染的突变巨细胞未能迁移到亡细胞,导致颗粒瘤分解和细菌生长的增加.
- 人类吸烟者的膜巨体显示出烟雾颗粒的溶解体积累,以及对Mycobacterium tuberculosis的迁移受损,反映出斑马鱼的表型.
结论:
- 在巨细胞中存储 lysosomal 损害了它们清除细胞残渣和有效迁移的能力,从而损害了对菌根菌感染的免疫反应.
- 斑马鱼模型突出显示了一种保存的机制,它将溶解体功能障碍与巨细胞功能障碍以及对菌根菌的敏感性增加联系在一起.
- 由于溶酶体储存而导致的巨细胞失能,如在吸烟者中观察到的,可能会导致他们患结核病的风险增加.
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