病原细菌和宿主天然免疫系统相互拮抗的机制研究  

Mechanisms of Interactions between Bacterial Pathogen and Host Innate Immune Defense System

作　　者：邵峰 

机构地区：[1]北京生命科学研究所,北京102206

出　　处：《中国基础科学》2012年第1期7-13,共7页China Basic Science

基　　金：科技部973计划项目(2010CB835400;2012CB518700);北京市科委资助

摘　　要：病原细菌通过阻断宿主细胞的重要生理过程来促进感染,进而引起各种疾病的发生。革兰氏阴性致病菌往往利用特殊的分泌系统(比如Ⅲ型分泌系统)向宿主细胞中注入毒力效应蛋白分子,这些效应蛋白采用非常复杂和精致的策略来阻断和控制宿主的信号转导通路,特别是那些在宿主天然免疫中具有重要功能的通路。最近刚刚提出的炎症小体(inflammasome)复合物被认为在巨噬细胞感受病原菌和拮抗感染的天然免疫反应中起着关键作用。我们实验室的研究一方面关注病原细菌是如何通过其分泌的毒力效应蛋白分子来阻断宿主的天然免疫信号转导通路的生物化学机制,另一方面我们也对巨噬细胞中的炎症小体通路是如何感受和抑制细菌感染的分子机制感兴趣。在前一个研究方向上,我们最近发现了包括来自肠致病大肠杆菌的NleE分子在内的一类细菌效应蛋白,它们具有一种全新的甲基转移酶活性,可以特异性地修饰宿主NF-κB信号通路中用于结合泛素链的TAB2/3分子。NleE通过甲基化修饰TAB2/3中鳌合锌离子的一个半胱氨酸从而导致TAB2/3失去结合泛素链的功能,并彻底阻断NF-κB介导的天然免疫炎症信号通路,这种修饰作用代表了一种全新的病原菌抑制宿主免疫防御反应的分子机制。在后一个研究方向上,我们最近鉴定了一个叫做NAIP的NOD样蛋白分子家族,实验发现和证明了NAIP是一类炎症小体的受体蛋白,可以直接识别来自病原菌的鞭毛蛋白或是病原菌Ⅲ型分泌系统的组成分子。NAIP家族分子在被这些细菌的模式分子活化后可以诱导NL-RC4炎症小体的激活,导致巨噬细胞发生炎症反应,进而在限制病原菌在宿主体内复制和感染中发挥重要作用。Bacterial pathogens disrupt key host cellular processes to facilitate infection and cause infectious diseases. Gram-negative bacteria often use specialized secretion systems such as the type Ⅲ secretion system to inject virulence effector proteins into host cells. These effectors employ sophisticated strategies to manipulate host signaling pathways, particularly those playing important roles in innate immune defense. The newly proposed inflammasome complex in macrophages senses bacterial products and serves as a critical mechanism in innate immune defense against bacterial infection. Research in our laboratory concerns the molecular mechanisms underlying how bacterial pathogens use injected virulence effectors to block host innate immune defense system as well as how the host uses the inflammasome pathway to sense and counteract bacterial infections. In the first direction, we recently discover a family of bacterial type Ⅲ effectors including NleE from Enteropathogenic E. coli that act as a novel type of methyltransferases to specifically methylate a zinc-coordinating cysteine in TAB2/3, the ubiquitin-chain sensory proteins in host NF-κB pathway. Cysteine methylation of TAB2/3 results in the loss of their ubiquitin-chain binding activity and the consequent shutdown of NF-κB-mediated pro-inflammatory responses, representing a novel mechanism in bacterial suppression of host defense signaling. In the other direction, we identify the NAIP family of NOD-like proteins as the inflammasome receptors for bacterial flagellin and type Ⅲ secretion apparatus components. Direct recognition of these bacterial products by NAIP receptors stimulates the NLRC4 inflammasome activation and macrophage inflammation, thereby restricting bacterial replication and infection.

关 键 词：细菌 天然免疫 机制 

分 类 号：R392[医药卫生—免疫学]