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Molecular Sensing of Chitin by Toll-like Receptors

Toll 样受体对甲壳素的分子传感

基本信息

批准号：
388534740
负责人：
Professor Dr. Alexander Weber, Ph.D.
金额：
--
依托单位：
Abteilung Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/388534740?language=en
关键词：
Molecular Sensing Chitin Toll like

项目摘要

Fungal infections and allergic asthma cause death and suffering in millions of patients worldwide and critically involve pattern recognition receptors (PRR)-mediated immune control. Dectin-1 is a cell-surface PRR for the microbe-associated molecular pattern (MAMP) beta-1,3-glucan, which is a major structural cell wall component in fungi and triggers phagocytosis of fungal pathogens and protective inflammatory responses. However, the PRR for chitin, a beta-1,4-N-acetyl-glucosamine (NAG) component of fungal cell walls and house dust mite allergen has remained controversial and so far no direct binding studies have been published. TLR2 is known to initiate potent immune responses by recognizing di- and triacylated lipopeptides in complex with TLR6 or TLR1, respectively. Although no fungal TLR2 ligand has been identified to date, TLR2 has been strongly implicated in murine infection models of and human patients suffering from the major pathogens Aspergillus and Candida, as well as allergic asthma. We have now identified TLR2 as the PRR directly binding and signaling to chitin. We observe that, whereas chitin chains containing more than 6 NAGs potently activate various human and murine immune cells, fragments containing only 4 or 5 NAGs are immunologically inactive but possess antagonistic activity. However, the mechanistic basis and immunological significance for agonism or antagonism of chitin NAGs via TLR2 remains elusive and is to be addressed here. Additionally, it remains unclear how TLR2 lipopeptide and chitin recognition may show differences and/or similarities in TLR1, TLR6, or potentially TLR10, co-receptor usage and the immunological outcomes of stimulation or antagonism. Since chitin represents the second most abundant polysaccharide in nature, is an immuno-activatory component linked to multiple human disease, affects Th1/Th2 skewing of adaptive immune responses and represents a potential novel vaccine adjuvant unraveling these principles of chitin recognition, signaling and immuno-regulation is of high basic and therapeutic interest.

真菌感染和过敏性哮喘导致全世界数百万患者死亡和痛苦，并严重涉及模式识别受体（PRR）介导的免疫控制。Dectin-1是微生物相关分子模式（MAMP）β-1，3-葡聚糖的细胞表面PRR，其是真菌中的主要结构细胞壁组分，并触发真菌病原体的吞噬作用和保护性炎症反应。然而，对于几丁质（真菌细胞壁的β-1，4-N-乙酰基-葡糖胺（NAG）组分）和屋尘螨过敏原的PRR仍然存在争议，迄今为止尚未发表直接结合研究。已知TLR 2通过分别识别与TLR 6或TLR 1复合的二酰化和三酰化脂肽来启动有效的免疫应答。尽管迄今为止还没有鉴定出真菌TLR 2配体，但TLR 2强烈地牵涉到患有主要病原体曲霉属和念珠菌属以及过敏性哮喘的小鼠感染模型和人类患者。我们现在已经确定TLR 2作为PRR直接结合几丁质并发出信号。我们观察到，而几丁质链含有超过6 NAG有效地激活各种人类和小鼠的免疫细胞，片段仅含有4或5 NAG是免疫无活性的，但具有拮抗活性。然而，通过TLR 2激动或拮抗甲壳素NAG的机制基础和免疫学意义仍然难以捉摸，有待于在这里解决。此外，还不清楚TLR 2脂肽和几丁质识别如何在TLR 1、TLR 6或潜在的TLR 10、共受体使用和刺激或拮抗的免疫学结果中显示差异和/或相似性。由于几丁质代表自然界中第二丰富的多糖，是与多种人类疾病相关的免疫活化组分，影响适应性免疫应答的Th 1/Th 2偏斜，并且代表潜在的新型疫苗佐剂，因此阐明几丁质识别、信号传导和免疫调节的这些原理具有高度的基础和治疗意义。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transkingdom mechanism of MAMP generation by chitotriosidase (CHIT1) feeds oligomeric chitin from fungal pathogens and allergens into TLR2-mediated innate immune sensing

壳三糖苷酶 (CHIT1) 产生 MAMP 的跨界机制将来自真菌病原体和过敏原的寡聚几丁质输送到 TLR2 介导的先天免疫传感中

DOI：
10.1101/2022.02.17.479713
发表时间：
期刊：
bioRxiv
影响因子：
0
作者：
Chang T-H;Cardona Gloria Y;Hellmann M;Greve C;Le Roy D;Kasper L;Hube B;Pusch S;Sorlie M;Tondervik A;Moerschbacher B;Weber ANR
通讯作者：
Weber ANR

The fungal ligand chitin directly binds TLR2 and triggers inflammation dependent on oligomer size