Human Toll-like receptor 4 responses to P. gingivalis are regulated by lipid A 1- and 4'-phosphatase activities.
Human Toll-like receptor 4 responses to P. gingivalis are regulated by lipid A 1- and 4'-phosphatase activities.
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DOI：
10.1111/j.1462-5822.2009.01349.x
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发表时间：
2009-11
影响因子：
3.4
通讯作者：
Darveau RP
中科院分区：
文献类型：
--
作者：
Coats SR;Jones JW;Do CT;Braham PH;Bainbridge BW;To TT;Goodlett DR;Ernst RK;Darveau RP
脂多糖（LPS）与Toll样受体4（TLR 4）结合后的信号转导是宿主对革兰氏阴性病原体感染的先天免疫应答的重要方面。在这里，我们描述了一种流行的人类细菌病原体逃避和破坏人类先天免疫系统的新分子机制。我们发现，口腔病原体牙龈卟啉单胞菌利用内源性脂质A1-和4 '-磷酸酶活性来修饰其LPS，产生免疫沉默的非磷酸化脂质A。这种独特的脂质A提供了一种非常有效的机制，该细菌采用这种机制来逃避TLR 4传感和抵抗阳离子抗菌肽的杀伤。此外，脂质A1-磷酸酶活性被氯高铁血红素抑制，氯高铁血红素是口腔中的重要营养素。具体而言，在高氯化血红素存在下生长的牙龈卟啉单胞菌产生充当有效TLR 4拮抗剂的脂质A。这些结果表明，脂质A1-去磷酸化的氯化血红素依赖性调节可以将牙龈卟啉单胞菌脂质A活性从TLR 4回避性转变为TLR 4抑制性，从而潜在地改变该细菌、局部微生物群落和宿主先天免疫系统之间的关键相互作用。
Signal transduction following binding of lipopolysaccharide (LPS) to Toll-like receptor 4 (TLR4) is an essential aspect of host innate immune responses to infection by Gram-negative pathogens. Here, we describe a novel molecular mechanism used by a prevalent human bacterial pathogen to evade and subvert the human innate immune system. We show that the oral pathogen, P. gingivalis, uses endogenous lipid A 1- and 4'-phosphatase activities to modify its LPS, creating immunologically silent, non-phosphorylated lipid A. This unique lipid A provides a highly effective mechanism employed by this bacterium to evade TLR4 sensing and to resist killing by cationic anti-microbial peptides. In addition, lipid A 1- phosphatase activity is suppressed by hemin, an important nutrient in the oral cavity. Specifically, P. gingivalis grown in the presence of high hemin produces lipid A that acts as a potent TLR4 antagonist. These results suggest that hemin-dependent regulation of lipid A 1-dephosphorylation can shift P. gingivalis lipid A activity from TLR4 evasive to TLR4 suppressive, potentially altering critical interactions between this bacterium, the local microbial community, and the host innate immune system.
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影响因子：
6.7
作者：
Munford, Robert S;Varley, Alan W
通讯作者：
Varley, Alan W
影响因子：
--
作者：
Kumada, H.;Haishima, Y.;Umemoto, T.
通讯作者：
Umemoto, T.
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.
影响因子：
3.4
作者：
Chen, Casey;Coats, Stephen R.;Darveau, Richard P.
通讯作者：
Darveau, Richard P.
影响因子：
3.5
作者：
HANIOKA, T;SHIZUKUISHI, S;TSUNEMITSU, A
通讯作者：
TSUNEMITSU, A