Lack of Lipid A Pyrophosphorylation and Functional lptA Reduces Inflammation by Neisseria Commensals
Lack of Lipid A Pyrophosphorylation and Functional lptA Reduces Inflammation by Neisseria Commensals
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DOI：
10.1128/iai.00506-12
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发表时间：
2012-11-01
影响因子：
3.1
通讯作者：
Jarvis, Gary A.
中科院分区：
文献类型：
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作者：
John, Constance M.;Liu, Mingfeng;Jarvis, Gary A.
免疫系统与共生奈瑟菌的相互作用仍然知之甚少。我们之前已经证明，低脂寡糖（LOS）的脂质A部分的磷酸乙醇胺在toll样受体4 （TLR4）信号传导中起重要作用。对于致病性奈瑟菌，磷酸乙醇胺通过脂质A特异性的磷酸乙醇胺转移酶添加到脂质A中，该酶由lptA编码。在这里，我们报告了所有8种共生奈瑟菌的基因组序列的南方杂交和生物信息学分析，证实了17种菌株中的15种不存在lptA，但在内酰胺奈瑟菌中存在。脂质A和完整LOS的质谱分析显示，缺乏lptA的共生物种的脂质A中缺乏焦磷酸化和磷酸乙醇胺化。与缺乏lptA的共生奈瑟菌菌株相比，人类THP-1单核细胞中的炎症信号在致病性中要大得多，并且对多粘菌素B的敏感性更高，这与缺乏磷酸乙醇胺一致。与其他共生菌不同的是，两种内酰胺乳杆菌共生菌株的整个细菌具有较低的炎症潜能，而它们的脂质A具有高水平的焦磷酸化和磷酸乙醇胺化，并诱导高水平的炎症信号，这支持了先前研究表明该物种通过改变脂质A以外的机制来支持共生。一种脑膜炎球菌lptA缺失突变体降低了炎症潜能，进一步说明了脂质A焦磷酸化和磷酸乙醇胺化在LOS生物活性中的重要性。总的来说，我们的研究结果表明，缺乏脂质A的焦磷酸化和磷酸乙醇胺化，通过降低LOS的炎症潜力，有助于大多数共生奈瑟菌菌株的免疫特权。
The interaction of the immune system with Neisseria commensals remains poorly understood. We have previously shown that phosphoethanolamine on the lipid A portion of lipooligosaccharide (LOS) plays an important role in Toll-like receptor 4 (TLR4) signaling. For pathogenic Neisseria, phosphoethanolamine is added to lipid A by the phosphoethanolamine transferase specific for lipid A, which is encoded by lptA. Here, we report that Southern hybridizations and bioinformatics analyses of genomic sequences from all eight commensal Neisseria species confirmed that lptA was absent in 15 of 17 strains examined but was present in N. lactamica. Mass spectrometry of lipid A and intact LOS revealed the lack of both pyrophosphorylation and phosphoethanolaminylation in lipid A of commensal species lacking lptA. Inflammatory signaling in human THP-1 monocytic cells was much greater with pathogenic than with commensal Neisseria strains that lacked lptA, and greater sensitivity to polymyxin B was consistent with the absence of phosphoethanolamine. Unlike the other commensals, whole bacteria of two N. lactamica commensal strains had low inflammatory potential, whereas their lipid A had high-level pyrophosphorylation and phosphoethanolaminylation and induced high-level inflammatory signaling, supporting previous studies indicating that this species uses mechanisms other than altering lipid A to support commensalism. A meningococcal lptA deletion mutant had reduced inflammatory potential, further illustrating the importance of lipid A pyrophosphorylation and phosphoethanolaminylation in the bioactivity of LOS. Overall, our results indicate that lack of pyrophosphorylation and phosphoethanolaminylation of lipid A contributes to the immune privilege of most commensal Neisseria strains by reducing the inflammatory potential of LOS.