Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.
Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.
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DOI：
10.1371/journal.ppat.1004215
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发表时间：
2014-07
期刊：
影响因子：
6.7
通讯作者：
Genco CA
中科院分区：
文献类型：
--
作者：
Slocum C;Coats SR;Hua N;Kramer C;Papadopoulos G;Weinberg EO;Gudino CV;Hamilton JA;Darveau RP;Genco CA
一些成功的病原体已经进化出逃避宿主防御的机制，导致建立持续和慢性感染。牙龈卟啉单胞菌（Porphyromonas gingivalis）是一种病原体，其诱导与局部炎性骨丢失和表现为动脉粥样硬化的全身性炎症相关的慢性低度炎症。牙龈卟啉单胞菌表达含有异质脂质A种类的非典型脂多糖（LPS）结构，其表现出Toll样受体-4（TLR 4）激动剂或拮抗剂活性，或者在TLR 4处是非活化的。在这项研究中，我们利用一系列牙龈卟啉单胞菌脂质A突变体来证明拮抗性脂质A结构使病原体能够逃避巨噬细胞中TLR 4介导的杀菌活性，从而导致全身性炎症。拮抗性脂质A的产生与诱导低水平的TLR 4依赖性促炎介质、炎性小体活化失败和巨噬细胞中细菌存活增加相关。ApoE−/−小鼠经口感染表达拮抗性脂质A的牙龈卟啉单胞菌菌株导致血管炎症、巨噬细胞积聚和动脉粥样硬化进展。相反，仅产生激动性脂质A的牙龈卟啉单胞菌菌株增加了促炎介质的水平，并以半胱天冬酶-11依赖性方式激活炎性小体，导致宿主细胞裂解和细菌存活减少。感染该菌株的ApoE−/−小鼠表现出减少的血管炎症、巨噬细胞积聚和动脉粥样硬化进展。值得注意的是，牙龈卟啉单胞菌诱导局部炎性骨丢失的能力与脂质A表达无关，表明该病原体诱导局部与全身炎症的不同机制。总的来说，我们的结果指出了牙龈卟啉单胞菌感染中非典型炎性小体激活的关键作用，并证明牙龈卟啉单胞菌逃避了TLR 4的免疫检测，促进了血管系统中的慢性炎症。这些研究支持了病原体介导的慢性炎症性疾病是由特定病原体介导的逃避策略导致的低度慢性炎症这一新兴概念。几种人类病原体表达结构上不同形式的脂质A，脂多糖（LPS）的内毒素部分，作为逃避宿主先天免疫检测和建立持续感染的策略。修饰的脂质A种类的表达促进病原体逃避Toll样受体-4（TLR 4）和非典型炎性体的宿主识别。革兰氏阴性口腔厌氧菌牙龈卟啉单胞菌表达作为TLR 4激动剂或拮抗剂起作用的脂质A结构，或者是免疫惰性的。目前尚不清楚牙龈卟啉单胞菌脂质A表达的调节如何有助于先天免疫识别、存活以及病原体诱导局部和全身炎症的能力。在这项研究中，我们证明，牙龈卟啉单胞菌表达拮抗剂脂质A种类的结果，在减弱生产的促炎介质和逃避非典型炎性小体激活，促进细菌在巨噬细胞中的生存。用这种菌株感染易患动脉粥样硬化的ApoE−/−小鼠导致血管系统慢性炎症的进展。值得注意的是，牙龈卟啉单胞菌诱导局部炎性骨丢失的能力与脂质A修饰无关，支持诱导局部与全身炎症的不同机制。我们的工作表明，逃避TLR 4的免疫检测有助于病原体的持续存在，并促进低度慢性炎症。
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. Several human pathogens express structurally divergent forms of lipid A, the endotoxic portion of lipopolysaccharide (LPS), as a strategy to evade host innate immune detection and establish persistent infection. Expression of modified lipid A species promotes pathogen evasion of host recognition by Toll-like receptor-4 (TLR4) and the non-canonical inflammasome. The Gram-negative oral anaerobe, Porphyromonas gingivalis, expresses lipid A structures that function as TLR4 agonists or antagonists, or are immunologically inert. It is currently unclear how modulation of P. gingivalis lipid A expression contributes to innate immune recognition, survival, and the ability of the pathogen to induce local and systemic inflammation. In this study, we demonstrate that P. gingivalis expression of antagonist lipid A species results in attenuated production of proinflammatory mediators and evasion of non-canonical inflammasome activation, facilitating bacterial survival in the macrophage. Infection of atherosclerosis-prone ApoE−/− mice with this strain resulted in progression of chronic inflammation in the vasculature. Notably, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A modifications, supporting distinct mechanisms for induction of local versus systemic inflammation. Our work demonstrates that evasion of immune detection at TLR4 contributes to pathogen persistence and facilitates low-grade chronic inflammation.
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影响因子：
3.4
作者：
Coats SR;Jones JW;Do CT;Braham PH;Bainbridge BW;To TT;Goodlett DR;Ernst RK;Darveau RP
通讯作者：
Darveau RP
影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
3.7
作者：
Cigana C;Curcurù L;Leone MR;Ieranò T;Lorè NI;Bianconi I;Silipo A;Cozzolino F;Lanzetta R;Molinaro A;Bernardini ML;Bragonzi A
通讯作者：
Bragonzi A
影响因子：
6.7
作者：
Cullen TW;Giles DK;Wolf LN;Ecobichon C;Boneca IG;Trent MS
通讯作者：
Trent MS
影响因子：
3.1
作者：
Al-Qutub, Montaser N.;Braham, Pamela H.;Darveau, Richard P.
通讯作者：
Darveau, Richard P.