Proinflammatory and proapoptotic activities associated with Bordetella pertussis filamentous hemagglutinin
Proinflammatory and proapoptotic activities associated with Bordetella pertussis filamentous hemagglutinin
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DOI：
10.1128/iai.69.4.2650-2658.2001
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发表时间：
2001-04-01
影响因子：
3.1
通讯作者：
Relman, DA
中科院分区：
文献类型：
--
作者：
Abramson, T;Kedem, H;Relman, DA
丝状血凝素（FHA）是一种显性的细胞表面相关的百日咳杆菌黏附素，认识到这种蛋白的大量分泌和细菌黏附素可能具有其他活性，促使了对FHA对人类巨噬细胞影响的评估。人巨噬细胞如U937细胞与FHA制剂孵育产生剂量依赖性的细胞毒性，24 h后95%的处理细胞死亡。通过四种独立的方法，这些细胞的死亡很大程度上归因于凋亡。在THP-1巨噬细胞样细胞、新鲜人外周血单核细胞源性巨噬细胞（MDM）和BEAS-2B人支气管上皮细胞中也观察到fha相关的凋亡。野生型百日咳杆菌感染MDM可在6小时内导致细胞凋亡，而fha缺陷衍生菌株感染的效果仅为50%。fha相关的细胞毒性发生之前，宿主细胞分泌肿瘤坏死因子α (tnf - α)，这是一种潜在的促凋亡因子。然而，用中和性抗tnf - cy单克隆抗体预处理细胞仅抑制16%的fha相关凋亡。另一方面，针对tnf - α受体1的阻断单克隆抗体抑制FHA相关的凋亡47.7% (P = 0.0001)，表明该受体可能在FHA激活的死亡途径中发挥作用。我们的体外数据表明，分泌的和与细胞相关的FHA在人单核细胞样细胞、MDM和支气管上皮细胞中引起促炎和促凋亡反应，并表明这种突出的毒力因子在百日咳-宿主相互作用中具有以前未被认识到的作用。
Filamentous hemagglutinin (FHA) is a dominant cell surface-associated Bordetella pertussis adhesin, Recognition that this protein is secreted in significant amounts and that bacterial adhesins may have other activities, prompted an assessment of FHA effects on human macrophages. Incubation of human macrophage like U937 cells with preparations of FHA resulted in dose-dependent cytotoxicity, with death of 95% of treated cells after 24 h. Based on the use of four independent methods, death of these cells could be largely attributed to apoptosis. FHA-associated apoptosis was also observed in THP-1 macrophage-like cells, fresh human peripheral blood monocyte derived macrophages (MDM), and BEAS-2B human bronchial epithelial cells. Infection of MDM with wild-type B. pertussis resulted in apoptosis within 6 h, while infection with an FHA-deficient derivative strain was only 50% as effective. FHA-associated cytotoxicity was preceded by host cell secretion of tumor necrosis factor alpha (TNF-alpha), a potential proapoptotic factor. However, pretreatment of cells with a neutralizing anti-TNF cy monoclonal antibody inhibited only 16% of the FHA-associated apoptosis. On the other hand, a blocking monoclonal antibody directed against TNF-alpha receptor 1 inhibited FHA-associated apoptosis by 47.7% (P = 0.0001), suggesting that this receptor may play a role in the death pathway activated by FHA. Our in vitro data indicate that secreted and cell-associated FHA elicits proinflammatory and proapoptotic responses in human monocyte-like cells, MDM, and bronchial epithelial cells and suggest a previously unrecognized role for this prominent virulence factor in the B. pertussis-host interaction.