Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome
Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome
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DOI：
10.1073/pnas.0913087107
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发表时间：
2010-02-16
影响因子：
11.1
通讯作者：
Aderem, Alan
中科院分区：
文献类型：
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作者：
Miao, Edward A.;Mao, Dat P.;Aderem, Alan
哺乳动物先天免疫系统使用toll样受体（TLRs）和nod - lrs （NLRs）来检测感染过程中的微生物成分。这些分子通常协同工作；例如，tlr可以刺激细胞因子IL-1 β和IL-18的产生，而某些nlr通过caspase 1触发它们随后的蛋白水解过程。革兰氏阴性菌使用III型分泌系统（T3SS）将毒力因子传递到宿主细胞的细胞质中，在那里它们调节细胞生理学以有利于病原体。我们发现NLRC4/Ipaf可以检测到鼠伤寒沙门氏菌（PrgJ）、假马氏伯克氏菌（BsaK）、大肠埃希菌（EprJ和EscI）、福氏志贺氏菌（MxiI）和铜绿假单胞菌（PscI）中T3SS装置的基体棒状成分（棒状蛋白）。这些杆状蛋白共享一个序列基序，这是NLRC4检测所必需的；在鞭毛蛋白中发现了一个相似的基序，该基序也被NLRC4检测到。鼠伤寒沙门氏菌有两个T3SS：编码杆状蛋白PrgJ的沙门氏菌致病性岛-1 （SPI1）和编码杆状蛋白SsaI的SPI2。虽然PrgJ可以被NLRC4检测到，但SsaI不能，而这种逃避是小鼠毒力所必需的。检测到T3SS装置的保守成分，可以通过单一途径对有毒细菌产生先天免疫反应，这与植物使用多个NB-LRR蛋白来检测T3SS效应器或其对细胞的影响的策略不同。此外，毒力机制的特异性检测允许区分致病性和非致病性细菌。
The mammalian innate immune system uses Toll-like receptors (TLRs) andNod-LRRs (NLRs) to detect microbial components during infection. Often these molecules work in concert; for example, the TLRs can stimulate the production of the proforms of the cytokines IL-1 beta and IL-18, whereas certain NLRs trigger their subsequent proteolytic processing via caspase 1. Gram-negative bacteria use type III secretion systems (T3SS) to deliver virulence factors to the cytosol of host cells, where they modulate cell physiology to favor the pathogen. We show here that NLRC4/Ipaf detects the basal body rod component of the T3SS apparatus (rod protein) from S. typhimurium (PrgJ), Burkholderia pseudomallei (BsaK), Escherichia coli (EprJ and EscI), Shigella flexneri (MxiI), and Pseudomonas aeruginosa (PscI). These rod proteins share a sequence motif that is essential for detection by NLRC4; a similar motif is found in flagellin that is also detected by NLRC4. S. typhimurium has two T3SS: Salmonella pathogenicity island-1 (SPI1), which encodes the rod protein PrgJ, and SPI2, which encodes the rod protein SsaI. Although PrgJ is detected by NLRC4, SsaI is not, and this evasion is required for virulence in mice. The detection of a conserved component of the T3SS apparatus enables innate immune responses to virulent bacteria through a single pathway, a strategy that is divergent from that used by plants in which multiple NB-LRR proteins are used to detect T3SS effectors or their effects on cells. Furthermore, the specific detection of the virulence machinery permits the discrimination between pathogenic and nonpathogenic bacteria.