Müller-Loennies Sven, Brade Lore, Brade Helmut
Division of Medical and Biochemical Microbiology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Parkallee 22, D-23845 Borstel, Germany.
Int J Med Microbiol. 2007 Sep;297(5):321-40. doi: 10.1016/j.ijmm.2007.04.002. Epub 2007 Jun 1.
Lipopolysaccharide (LPS, endotoxin) elicits an immune reaction which is responsible for many of the harmful effects seen in septic shock patients. The eradication of bacteria by antibiotics is insufficient to resolve the pathology due to the lack of LPS neutralization. LPS-neutralizing antibodies have been described; however, these were specific for the serotype of the infecting bacteria and thus not useful for the treatment of septic shock patients. Structural analyses revealed that the LPS structures of Escherichia coli and Salmonella are structurally conserved in the inner core region. Using whole LPS and a panel of neoglycoconjugates containing purified LPS oligosaccharides, which we have obtained from all E. coli core types (K-12, R1, R2, R3 and R4), Salmonella enterica, and the mutant strain E. coli J-5, we have identified an epitope which is bound with high affinity by the monoclonal antibody WN1 222-5, which has been shown previously shown to be cross-reactive against a large collection of blood, fecal, and urinary isolates of E. coli, S. enterica, some Citrobacter, independently of the serotype [Di Padova, F.E., Brade, H., Barclay, G.R., Poxton, I.R., Liehl, E., Schuetze, E., Kocher, H.P., Ramsay, G., Schreier, M.H., McClelland, D.B., Rietschel, E.T., 1993. A broadly cross-protective monoclonal antibody binding to Escherichia coli and Salmonella lipopolysaccharides. Infect. Immun. 61, 3863-3872]. Importantly, WN1 222-5 was protective in various models of endotoxic shock. The minimal structural element necessary for high-affinity binding consists of R(1)-alpha-d-Glcp-(1-->3)-[l-alpha-d-Hepp-(1-->7)]-l-alpha-d-Hepp 4P-(1-->3)-R(2) (R(1), R(2)=additional sugars of LPS) in which the side-chain heptose and the 4-phosphate on the branched heptose are the main determinants of the epitope. Additional sugars of the outer core (R(1)) enhance the affinity, whereas loss of an intact Kdo region and/or lipid A (R(2)) prevent binding. The identification of the epitope provides the structural basis for the rational development of a potential vaccine against E. coli LPS.
脂多糖（LPS，内毒素）引发免疫反应，这是脓毒症休克患者出现许多有害影响的原因。由于缺乏LPS中和作用，使用抗生素根除细菌不足以解决病理问题。已经描述了LPS中和抗体；然而，这些抗体对感染细菌的血清型具有特异性，因此对脓毒症休克患者的治疗没有用处。结构分析表明，大肠杆菌和沙门氏菌的LPS结构在内核区域结构保守。我们使用全LPS和一组含有纯化LPS寡糖的新糖缀合物（我们从所有大肠杆菌核心类型（K-12、R1、R2、R3和R4）、肠炎沙门氏菌和突变株大肠杆菌J-5中获得），鉴定出一个表位，单克隆抗体WN1 222-5能以高亲和力与之结合，先前已证明该抗体对大量大肠杆菌、肠炎沙门氏菌、一些柠檬酸杆菌的血液、粪便和尿液分离株具有交叉反应性，与血清型无关[迪帕多瓦，F.E.，布拉德，H.，巴克利，G.R.，波克斯顿，I.R.，利尔，E.，舒策，E.，科赫尔，H.P.，拉姆齐，G.，施赖尔，M.H.，麦克莱兰，D.B.，里特舍尔，E.T.，1993。一种与大肠杆菌和沙门氏菌脂多糖结合的具有广泛交叉保护作用的单克隆抗体。感染与免疫。61，3863 - 3872]。重要的是，WN1 222-5在各种内毒素休克模型中具有保护作用。高亲和力结合所需的最小结构元件由R(1)-α-d-葡萄糖-(1→3)-[l-α-d-庚糖-(1→7)]-l-α-d-庚糖4P-(1→3)-R(2)组成（R(1)、R(2)=LPS的其他糖类），其中侧链庚糖和分支庚糖上的4-磷酸是表位的主要决定因素。外核的其他糖类（R(1)）增强亲和力，而完整的Kdo区域和/或脂质A（R(2)）的缺失会阻止结合。该表位的鉴定为合理开发针对大肠杆菌LPS的潜在疫苗提供了结构基础。
