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Carcinoembryonic Antigen Family Receptor Specificity of Neisseria meningitidis Opa Variants Influences Adherence to and Invasion of Proinflammatory Cytokine-Activated Endothelial Cells

机译:脑膜炎奈瑟氏菌Opa变种的癌胚抗原家族受体特异性影响促炎性细胞因子激活的内皮细胞的粘附和侵袭。

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The carcinoembryonic antigen (CEA) family member CEACAM1 (previously called biliary glycoprotein or CD66a) was previously shown to function as a receptor that can mediate the binding of Opa protein-expressing Neisseria meningitidis to both neutrophils and epithelial cells. Since neutrophils and polarized epithelia have both been shown to coexpress multiple CEACAM receptors, we have now extended this work to characterize the binding specificity of meningococcal Opa proteins with other CEA family members. To do so, we used recombinant Escherichia coli expressing nine different Opa variants from three meningococcal strains and stably transfected cell lines expressing single members of the CEACAM family. These infection studies demonstrated that seven of the nine Opa variants bound to at least one CEACAM receptor and that binding to each of these receptors is sufficient to trigger the Opa-dependent bacterial uptake by these cell lines. The other two Opa variants do not appear to bind to either CEACAM receptors or heparan sulfate proteoglycan receptors, which are bound by some gonococcal Opa variants, thus implying a novel class of Opa proteins. We have also extended previous studies by demonstrating induction of CEACAM1 expression after stimulation of human umbilical vein endothelial cells with the proinflammatory cytokine tumor necrosis factor alpha, which is present in high concentrations during meningococcal disease. This induced expression of CEACAM1 leads to an increased Opa-dependent bacterial binding and invasion into the primary endothelia, implying that these interactions may play an important role in the pathogenesis of invasive meningococcal disease.
机译:先前显示,癌胚抗原(CEA)家族成员CEACAM1(以前称为胆汁糖蛋白或CD66a)起受体的作用,可以介导表达Opa蛋白的脑膜炎奈瑟氏球菌与嗜中性粒细胞和上皮细胞结合。由于嗜中性粒细胞和极化的上皮细胞均已显示出共表达多种CEACAM受体,因此我们现在扩展了这项工作,以表征脑膜炎球菌Opa蛋白与其他CEA家族成员的结合特异性。为此,我们使用了重组大肠杆菌,该大肠杆菌表达了来自三种脑膜炎球菌菌株的九种不同的Opa变体,并稳定表达了CEACAM家族成员的转染细胞系。这些感染研究表明,九个Opa变体中的七个与至少一个CEACAM受体结合,并且与每个这些受体的结合足以触发这些细胞系对Opa的依赖性细菌吸收。其他两个Opa变体似乎不与CEACAM受体或硫酸乙酰肝素蛋白聚糖受体结合,后者被某些淋球菌Opa变体结合,因此暗示了一类新的Opa蛋白。我们还通过证明用促炎性细胞因子肿瘤坏死因子α刺激人脐静脉内皮细胞后CEACAM1表达的诱导,扩展了先前的研究,后者在脑膜炎球菌病期间呈高浓度存在。 CEACAM1的这种诱导表达导致Opa依赖性细菌结合增加并侵入初级内皮细胞,这意味着这些相互作用可能在侵袭性脑膜炎球菌的发病机理中起重要作用。

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