Toll样受体5和鞭毛蛋白的相互作用影响宿主区分病原菌和益生菌（英文稿）

Host discriminates between probiotics and pathogens: impact of toll like receptor 5-flagellin interaction and evolution

摘要:

【目的】大量的证据表明机体正常的免疫活动在很大程度上依赖于免疫系统和肠道菌群的相互作用，具体表现为免疫系统对病原菌进行免疫清除而对益生菌耐受。其中，免疫系统的Toll样受体(Toll-like receptors，TLRs)和来自肠道菌群的微生物相关的分子模型(Microorganism associated molecular patterns，MAMPs)被认为在宿主免疫系统对病原菌和益生菌的区分中发挥了重要作用，因为TLRs对MAMPs的识别能够激活先天性和获得性免疫反应。在TLRs对MAMPs的识别中，只有TLR5对细菌鞭毛蛋白的识别是基于蛋白-蛋白的相互作用，比较容易对其结合方式进行研究。因此，我们研究的主要目的就是要确定TLR5与鞭毛蛋白的相互作用是如何影响宿主区分病原菌和益生菌的。【方法】构建了多种肠道细菌(包括益生菌和病原菌)鞭毛蛋白的系统发育树，并比对了鞭毛蛋白的TLR5识别序列。【结果】发现病原菌和益生菌的鞭毛蛋白序列有所不同，尤其是TLR5结合并识别的鞭毛蛋白位点。【结论】病原菌和益生菌不同的鞭毛蛋白识别区域可能是鞭毛细菌适应TLR5识别下生存的结果，据此宿主能够对病原菌和益生菌进行区分。此外，相关研究表明TLRs在肠上皮细胞的分布具有基底侧和顶端的两极性，能够分别引发对病原菌的免疫反应和对益生菌的免疫耐受，从而抵御病原菌的入侵感染、与益生菌和平共处。鞭毛蛋白和TLR5蛋白的相互作用反映了肠道菌群和免疫系统在分子层面的相互作用和共同进化，是宿主区分病原菌和益生菌的分子机制之一。

Abstract:

[Objective] Data from ample studies support the idea that the immune homeostasis is crucially dependent on a cross-talk between host immune system and enteric flora in which the host recognizes and responses distinctively to probiotic and pathogenic bacteria. The toll-like receptors (TLRs) and microorganism associated molecular patterns (MAMPs) may play a major role in the host discrimination between probiotics and pathogens, as the recognition of MAMPs by TLRs can activate innate immune response and prime the adaptive immune system. In the TLRs family, TLR5 that responds to flagellin is the only protein-binding TLR, it’s much easier to study the flagellin-TLR5 interaction structurally and functionally. The overall aim of this study was to test for a possible contribution of the flagellin-TLR5 crosstalk to the host discrimination between probiotic and pathogenic bacteria. [Methods] Using flagellin protein sequences from probiotic and pathogenic bacteria living in gastrointestinal tract, we firstly constructed a phylogenetic tree of flagellin proteins and then aligned the flagellin protein sequences in TLR5 recognition region between probiotic and pathogenic bacteria. [Results] We found that probiotic and pathogenic bacteria differed in flagellin protein sequence, particularly in the TLR5 recognition sites. [Conclusion] Acclimatization to TLR5 recognition may result in the different TLR5 recognition sites on flagellin between pathogens and probiotics. Moreover, previous studies show that stimulation of basolaterally expressed TLRs results in inflammatory response, but activation of apically expressed TLRs leads to inhibition of the proinflammatory response. Altogether, our findings provide preliminary but encouraging evidence for the existence of crosstalk between flagellin and TLR5 which may be one of the mechanisms for the host discrimination between probiotics and pathogens.