引起慢性口腔感染牙周疾病的病原体-牙龈卟啉单胞菌不仅可以引发牙龈的局部炎症，而且该病原菌还和动脉粥样硬化（atherosclerosis，AS）风险的增加直接相关，近日，刊登在国际杂志PLoS Pathogens上的一篇研究论文中，来自美国波士顿大学医学院的研究人员通过研究揭示了牙龈卟啉单胞菌入侵机体免疫系统诱导口腔炎症及其它疾病的分子机制。
　　牙龈卟啉单胞菌的细胞外层也包含着许多糖类和脂质，千百年来哺乳动物免疫系统已经进化到可以识别部分的细菌细胞包被，从而诱发机体的多重免疫反应，作为宿主和细菌之间的“军备竞赛”，包括牙龈卟啉单胞菌在内的许多革兰氏阴性菌，其都会采取一定的策略来改变其细胞外被来避免免疫防御。
　　研究者Caroline Attardo Genco表示，这项研究中我们重点对牙龈卟啉单胞菌细胞外被表达的一种特殊脂质-lipidA（脂质A）进行研究，其可以和宿主免疫系统的关键调节子TLR4相互作用；牙龈卟啉单胞菌可以产生一系列不同的脂质A，研究者想去阐明其如何修饰宿主免疫系统来导致病原菌生存以及引发炎症。
　　文章中，研究者通过遗传修饰，构建了携带有两个不同脂质A版本的牙龈卟啉单胞菌，这种遗传构建的牙龈卟啉单胞菌就要么产生可以激活TLR4的脂质A（激动剂），要么产生可以阻断TLR4的脂质A（拮抗剂）；利用这些菌株，研究人员发现，产生拮抗剂脂质A的细菌可以帮助细菌对宿主的免疫杀伤作用产生耐受性，这就可以帮助细菌在巨噬细胞存在的情况下生存。
　　当研究者利用拮抗TLR4的牙龈卟啉单胞菌感染易于形成动脉粥样硬化的小鼠后，结果发现，细菌加速了小鼠血管中炎性的形成而且促进了动脉粥样硬化的发生；相反，诱导局部炎症骨质缺失的牙龈卟啉单胞菌则并不依赖于脂质A变体的存在，这就表明诱导局部或者系统性炎症之间存在不同的机制。
　　最后研究人员表示，牙龈卟啉单胞菌可以修饰脂质A的结构来入侵宿主机体并且建立慢性感染，从而引发持续性的系统低级炎症，尤其是在革兰氏阴性杆菌中，逃脱TLR4介导的宿主免疫系统的牙龈卟啉单胞菌往往会在血管系统局部感染较远的位点引发炎症。
　　原文摘要：
Distinct Lipid A Moieties Contribute to Pathogen-Induced Site-Specific Vascular Inflammation
Several successful pathogens have evolved mechanisms to evade host defense， resulting in the establishment of persistent and chronic infections. One such pathogen， Porphyromonas gingivalis， induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. P. gingivalis expresses an atypical lipopolysaccharide （LPS） structure containing heterogeneous lipid A species， that exhibit Toll-like receptor-4 （TLR4） agonist or antagonist activity， or are non-activating at TLR4. In this study， we utilized a series of P. gingivalis lipid A mutants to demonstrate that antagonistic lipid A structures enable the pathogen to evade TLR4-mediated bactericidal activity in macrophages resulting in systemic inflammation. Production of antagonistic lipid A was associated with the induction of low levels of TLR4-dependent proinflammatory mediators， failed activation of the inflammasome and increased bacterial survival in macrophages. Oral infection of ApoE−/− mice with the P. gingivalis strain expressing antagonistic lipid A resulted in vascular inflammation， macrophage accumulation and atherosclerosis progression. In contrast， a P. gingivalis strain producing exclusively agonistic lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner， resulting in host cell lysis and decreased bacterial survival. ApoE−/− mice infected with this strain exhibited diminished vascular inflammation， macrophage accumulation， and atherosclerosis progression. Notably， the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A expression， indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. Collectively， our results point to a pivotal role for activation of the non-canonical inflammasome in P. gingivalis infection and demonstrate that P. gingivalis evades immune detection at TLR4 facilitating chronic inflammation in the vasculature. These studies support the emerging concept that pathogen-mediated chronic inflammatory disorders result from specific pathogen-mediated evasion strategies resulting in low-grade chronic inflammation.

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