Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells
Regulation of interactions of Gram-negative bacterial endotoxins with mammalian cells
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DOI：
10.1007/s12026-007-0069-0
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Weiss, Jerrold P.
中科院分区：
文献类型：
--
作者：
Gioannini, Theresa L.;Weiss, Jerrold P.
宿主对许多入侵的革兰氏阴性菌(GNB)的防御依赖于对内毒素(脂多糖)的天然免疫识别，内毒素是GNB特有的表面糖脂。宿主对内毒素的反应必须高度敏感，但必须是自我限制的。在哺乳动物中，通过内毒素与几种不同的细胞外和细胞表面蛋白-内毒素结合蛋白(LBP)、CD14、MD-2和Toll样受体(TLR)4-的有序相互作用来实现最佳的敏感性，反映了特定的蛋白质-内毒素和蛋白质-蛋白质相互作用的要求。这种复杂的反应途径也提供了许多方法来减轻内毒素驱动的炎症，并可以解释内毒素结构的差异如何改变宿主的反应性，从而改变宿主-GNB相互作用的结果。我们研究的主要目标是更好地了解：(1)特定宿主-内毒素相互作用的结构基础；(2)宿主内毒素结合蛋白之间的功能多样性；(3)各种内毒素结合蛋白的作用如何被调节，以允许宿主对GNB感染做出最佳反应。此外，鉴定出一种水溶性内毒素：MD-2复合体，它取决于内毒素或MD-2的结构，具有强大的TLR4激动剂或拮抗剂特性，为免疫调节提供了新的药理学方法。
Host defense against many invading Gram-negative bacteria (GNB) depends on innate immune recognition of endotoxin (lipopolysaccharides, LPS), unique surface glycolipids of GNB. Host responses to endotoxin must be highly sensitive but self-limited. In mammals, optimal sensitivity is achieved by ordered interactions of endotoxin with several different extracellular and cell surface proteins-the LPS-binding protein (LBP), CD14, MD-2, and Toll-like receptor (TLR) 4-reflecting the requirement for specific protein-endotoxin and protein-protein interactions. This complex reaction pathway also provides many ways to attenuate endotoxin-driven inflammation and can explain how differences in endotoxin structure, either intrinsic among GNB or induced by metabolic remodeling, can alter host responsiveness and thus the outcome of host-GNB interactions. Major goals of our research are to better understand: (1) the structural bases of specific host-endotoxin interactions; (2) functional diversity among host endotoxin-binding proteins; and (3) how the actions of various endotoxin-binding proteins are regulated to permit optimal host responses to GNB infection. In addition, the identification of a water-soluble endotoxin:MD-2 complex that, depending on the structure of endotoxin or MD-2, has potent TLR4 agonist or antagonist properties suggests novel pharmacologic approaches to immuno-modulation.