Principles of extra- and intracellular chitin perception by mammalian pattern recognition receptors

哺乳动物模式识别受体感知细胞外和细胞内几丁质的原理

基本信息

项目摘要

Chitin, a hydrophobic polymer of β-1,4-linked N-acetylglucosamine (GlcNAc), is abundant in nature and can be found e.g. in the cell wall of fungi, the exoskeletons of arthropods such as crustaceans and insects, and nematodes. However, chitin does not exist in mammals and plants. In these organisms, chitin is a typical microbe-associated molecular pattern (MAMP), as evidenced by the existence of chitin-mediated activation of immune responses through pattern recognition receptors (PRRs). In humans the consequent PRR-mediated inflammatory responses have been associated with fungal infections and allergic asthma. During initial exposure, the mammalian host typically encounters chitin in a highly polymeric and insoluble form – e. g. fragments of the exoskeleton of house dust mites or the cell wall of pathogenic fungi like C. albicans or C. neoformans – and this polymeric insoluble chitin has been considered immunologically inert. However, we previously showed that in humans, sensing of soluble, oligomeric chitin is mediated by Toll-like receptor (TLR) 2 in immune cells, whereas work by others demonstrated FIBCD1 or LYSMD3 are involved in epithelial cells. We recently found that TLR2 signaling also employs LBP, CD14 and TLR1 and can be activated by diffusible ligands provided by the host endochitinase, CHIT1. These newly discovered sensing pathways are highly reminiscent of chitin perception in plants, where the cell-surface receptors CERK1 and its co-receptor CEBiP detect chitin oligomers generated by host chitinases. However, in the structure-function relationships (e.g. degree and pattern of acetylation) and the regulation of chitin sensing by the mammalian CHIT1-TLR system await systematic exploration for a better understanding and, possibly, targeting of extracellular chitin sensing. Moreover, recent advances in carbohydrate synthesis open the possibility for systematic analysis of custom-made, non-natural synthetic oligomers for agonistic and antagonistic immune-regulatory properties in mammalian systems. Finally, the intriguing notion of cytosolic chitin sensing in the context of intracellular fungal pathogens like C. neoformans remains open but could be vital for understanding immune responses triggered by intracellular fungal pathogens. Based on the preliminary data generated together with other consortium members and with further partnerships and tools available within this priority program, these open questions will be addressed in both human and murine cellular systems, hoping to delineate a ‘code’ of what determines extra- and intracellular immune stimulation by chitin in mammalia. The knowledge gained in the first funding phase could then be applied to explain and modulate/prevent immune reactions in the context of chito-based biomaterials and/or exploited to purpose-build materials with specific immune-agonistic or -antagonistic properties.
甲壳素是一种β-1,4-连接的N-乙酰葡萄糖胺(GlcNAc)的疏水聚合物,在自然界中含量丰富,可在真菌的细胞壁、节肢动物(如甲壳动物和昆虫)的外骨骼以及线虫中发现。但是,甲壳质并不存在于哺乳动物和植物中。在这些生物体中,几丁质是一种典型的微生物相关分子模式(MAMP),如通过模式识别受体(PRRs)存在几丁质介导的免疫应答的激活所证明的。在人类中,随后发生的PRR介导的炎症反应与真菌感染和过敏性哮喘相关。在最初的暴露过程中,哺乳动物宿主通常遇到高度聚合和不溶性形式的几丁质. G.屋尘螨的外骨骼的碎片或病原真菌如C. albicans)和非白念珠菌(C.并且这种聚合的不溶性壳多糖被认为是免疫惰性的。然而,我们先前已经表明,在人类中,可溶性寡聚几丁质的感知是由免疫细胞中的Toll样受体(TLR)2介导的,而其他人的工作表明,FIBCD 1或LYSMD 3参与上皮细胞。我们最近发现TLR 2信号传导也使用LBP、CD 14和TLR 1,并且可以被宿主几丁质内切酶CHIT 1提供的扩散配体激活。这些新发现的传感途径高度让人想起植物中的几丁质感知,其中细胞表面受体CERK 1及其辅助受体CEBiP检测宿主几丁质酶产生的几丁质寡聚体。然而,在结构-功能关系(例如乙酰化的程度和模式)和哺乳动物CHIT 1-TLR系统对几丁质感应的调节方面,有待于系统地探索,以便更好地理解,并可能靶向胞外几丁质感应。此外,碳水化合物合成的最新进展为系统分析定制的、非天然合成寡聚体在哺乳动物系统中的激动和拮抗免疫调节特性提供了可能。最后,在胞内真菌病原体如C。但对于理解由细胞内真菌病原体引发的免疫应答可能是至关重要的。基于与其他联盟成员一起产生的初步数据,以及在该优先项目中可用的进一步合作伙伴关系和工具,将在人和鼠细胞系统中解决这些开放性问题,希望描绘出哺乳动物中几丁质决定细胞外和细胞内免疫刺激的“代码”。在第一个供资阶段获得的知识可用于解释和调节/预防基于壳聚糖的生物材料背景下的免疫反应,和/或用于构建具有特定免疫激动或拮抗特性的材料。

项目成果

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Professor Dr. Alexander Weber, Ph.D.其他文献

Professor Dr. Alexander Weber, Ph.D.的其他文献

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{{ truncateString('Professor Dr. Alexander Weber, Ph.D.', 18)}}的其他基金

ImMiGeNe - Interplay of immune parameters, microbiota and host genetics during childhood stem cell transplantation
ImMiGeNe - 儿童干细胞移植过程中免疫参数、微生物群和宿主遗传学的相互作用
  • 批准号:
    433115696
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Molecular Role of Bruton’s Tyrosine Kinase (BTK) in NLRP3 Inflammasome Activation
布鲁顿酪氨酸激酶 (BTK) 在 NLRP3 炎症小体激活中的分子作用
  • 批准号:
    414795436
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Molecular Sensing of Chitin by Toll-like Receptors
Toll 样受体对甲壳素的分子传感
  • 批准号:
    388534740
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Structure-function relationships of Toll-like receptors, key mediators of antiviral innate immunity, in Human Papillomavirus 16 infection and cervical cancer
Toll 样受体(抗病毒先天免疫的关键介质)在人乳头瘤病毒 16 感染和宫颈癌中的结构-功能关系
  • 批准号:
    23262953
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
    Independent Junior Research Groups
STAPHEX II: Dissecting Staphylococcus aureus macrophage exit
STAPHEX II:解剖金黄色葡萄球菌巨噬细胞出口
  • 批准号:
    446507619
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes

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BET蛋白家族溴结构域抑制剂治疗恶性胰腺导管内乳头状黏液瘤及相关耐药机制的研究
  • 批准号:
    81702412
  • 批准年份:
    2017
  • 资助金额:
    21.0 万元
  • 项目类别:
    青年科学基金项目

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responsiveness of nasal ciliated cell for extra- or intracellular ionic environmental change
鼻纤毛细胞对细胞外或细胞内离子环境变化的反应
  • 批准号:
    18K09325
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Design of Non-viral Gene Carriers that Overcome Extra- and Intracellular Barriers
克服细胞外和细胞内屏障的非病毒基因载体的设计
  • 批准号:
    8329751
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Design of Non-viral Gene Carriers that Overcome Extra- and Intracellular Barriers
克服细胞外和细胞内屏障的非病毒基因载体的设计
  • 批准号:
    8128093
  • 财政年份:
    2011
  • 资助金额:
    --
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Synergistic extra and intracellular recognition of F. tularensis
土拉弗朗西斯胞外和胞内的协同识别
  • 批准号:
    8110762
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
Synergistic extra and intracellular recognition of F. tularensis
土拉弗朗西斯胞外和胞内的协同识别
  • 批准号:
    7589310
  • 财政年份:
    2008
  • 资助金额:
    --
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Synergistic extra and intracellular recognition of F. tularensis
土拉弗朗西斯胞外和胞内的协同识别
  • 批准号:
    7749571
  • 财政年份:
    2008
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    --
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New Gene Vectors for Cystic Fibrosis (CF): Extra- & Intracellular Barriers
囊性纤维化 (CF) 的新基因载体:Extra-
  • 批准号:
    7483583
  • 财政年份:
    2007
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    --
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New Gene Vectors for Cystic Fibrosis (CF): Extra- & Intracellular Barriers
囊性纤维化 (CF) 的新基因载体:Extra-
  • 批准号:
    7317048
  • 财政年份:
    2007
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New Gene Vectors for Cystic Fibrosis (CF): Extra- & Intracellular Barriers
囊性纤维化 (CF) 的新基因载体:Extra-
  • 批准号:
    7619127
  • 财政年份:
    2007
  • 资助金额:
    --
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New Gene Vectors for Cystic Fibrosis (CF): Extra- & Intracellular Barriers
囊性纤维化 (CF) 的新基因载体:Extra-
  • 批准号:
    7828118
  • 财政年份:
    2007
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