Pridmore A C, Wyllie D H, Abdillahi F, Steeghs L, van der Ley P, Dower S K, Read R C
Division of Molecular and Genetic Medicine, Royal Hallamshire Hospital, University of Sheffield, Sheffield, United Kingdom.
J Infect Dis. 2001 Jan 1;183(1):89-96. doi: 10.1086/317647. Epub 2000 Nov 10.
Meningococcal disease severity correlates with circulating concentrations of lipopolysaccharide (LPS) and proinflammatory cytokines. Disruption of the lpxA gene of Neisseria meningitidis generated a viable strain that was deficient of detectable LPS. The potency of wild-type N. meningitidis to elicit tumor necrosis factor (TNF)-alpha production by human monocyte-derived macrophages was approximately 10-fold greater than that of the lpxA mutant. Killed wild-type N. meningitidis and its soluble products induced interleukin (IL)-8 and TNF-alpha secretion by transfected HeLa cells expressing Toll-like receptor (TLR) 4/MD2, but the lpxA mutant was inactive via this pathway. In contrast, both strains induced IL-8 promoter activity in TLR2-transfected HeLa cells. These data provide evidence that N. meningitidis contains components other than LPS that can elicit biological responses via pathways that are independent of the TLR4/MD2 receptor system, and TLR2 is one of these alternate pathways. These findings have implications for future therapeutic strategies against meningococcal disease on the basis of the blockade of TLRs and the modulation of LPS activity.
脑膜炎球菌病的严重程度与循环中的脂多糖（LPS）和促炎细胞因子浓度相关。脑膜炎奈瑟菌lpxA基因的破坏产生了一种可存活的菌株，该菌株缺乏可检测到的LPS。野生型脑膜炎奈瑟菌诱导人单核细胞衍生巨噬细胞产生肿瘤坏死因子（TNF）-α的能力比lpxA突变体高约10倍。经热灭活的野生型脑膜炎奈瑟菌及其可溶性产物可诱导表达Toll样受体（TLR）4/MD2的转染HeLa细胞分泌白细胞介素（IL）-8和TNF-α，但lpxA突变体通过该途径无活性。相反，两种菌株均可诱导TLR2转染的HeLa细胞中IL-8启动子活性。这些数据证明，脑膜炎奈瑟菌除LPS外还含有其他成分，这些成分可通过独立于TLR4/MD2受体系统的途径引发生物学反应，而TLR2是这些替代途径之一。这些发现对基于TLR阻断和LPS活性调节的未来抗脑膜炎球菌病治疗策略具有启示意义。
