Complement Regulator Factor H Mediates a Two-step Uptake of Streptococcus pneumoniae by Human Cells
Complement Regulator Factor H Mediates a Two-step Uptake of Streptococcus pneumoniae by Human Cells
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DOI：
10.1074/jbc.m110.142703
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发表时间：
2010-07-23
影响因子：
4.8
通讯作者：
Hammerschmidt, Sven
中科院分区：
文献类型：
--
作者：
Agarwal, Vaibhav;Asmat, Tauseef M.;Hammerschmidt, Sven
肺炎链球菌是一种人类病原体，它将补体调节因子 H 募集到其细菌细胞表面。细菌 PspC 蛋白通过短共有重复序列 (SCR) 8-11 和 SCR19-20 结合 H 因子。在这项研究中，我们定义了细菌结合的 H 因子如何通过两步过程促进肺炎球菌粘附在上皮细胞或人多形核白细胞 (PMN) 上并被其吸收。首先，肝素和硫酸皮肤素显着降低了肺炎球菌对上皮细胞的粘附。然而，没有一种糖胺聚糖影响 H 因子与肺炎球菌的结合。识别 H 因子 SCR19-20 的单克隆抗体可抑制肺炎球菌与人上皮细胞的粘附，这表明 H 因子的 C 末端糖胺聚糖结合区介导了肺炎球菌与人细胞之间的接触。阻断 PMN 或表达 CR3 的上皮细胞的整合素 CR3 受体（即 CD11b 和 CD18）可显着减少肺炎球菌与两种细胞类型的相互作用。同样，另一种来自白色念珠菌的 CR3 配体 Pra1 可以阻断肺炎球菌与 PMN 的相互作用。引人注目的是，Pra1 还抑制肺上皮细胞对肺炎球菌的摄取，但不抑制其粘附。此外，H因子包被的肺炎球菌的侵袭需要宿主细胞肌动蛋白微丝的动力学，并受到蛋白酪氨酸激酶和磷脂酰肌醇3-激酶抑制剂的影响。总之，肺炎球菌通过 H 因子进入宿主细胞基于两步机制。 H因子包被的肺炎球菌的第一次接触是由人类细胞表面表达的糖胺聚糖介导的，第二步，即肺炎球菌的摄取，是由整合素介导的，并依赖于宿主信号分子，例如磷脂酰肌醇3-激酶。
Streptococcus pneumoniae, a human pathogen, recruits complement regulator factor H to its bacterial cell surface. The bacterial PspC protein binds Factor H via short consensus repeats (SCR) 8-11 and SCR19-20. In this study, we define how bacterially bound Factor H promotes pneumococcal adherence to and uptake by epithelial cells or human polymorphonuclear leukocytes (PMNs) via a two-step process. First, pneumococcal adherence to epithelial cells was significantly reduced by heparin and dermatan sulfate. However, none of the glycosaminoglycans affected binding of Factor H to pneumococci. Adherence of pneumococci to human epithelial cells was inhibited by monoclonal antibodies recognizing SCR19-20 of Factor H suggesting that the C-terminal glycosaminoglycan-binding region of Factor H mediates the contact between pneumococci and human cells. Blocking of the integrin CR3 receptor, i.e. CD11b and CD18, of PMNs or CR3-expressing epithelial cells reduced significantly the interaction of pneumococci with both cell types. Similarly, an additional CR3 ligand, Pra1, derived from Candida albicans, blocked the interaction of pneumococci with PMNs. Strikingly, Pra1 inhibited also pneumococcal uptake by lung epithelial cells but not adherence. In addition, invasion of Factor H-coated pneumococci required the dynamics of host-cell actin microfilaments and was affected by inhibitors of protein-tyrosine kinases and phosphatidylinositol 3-kinase. In conclusion, pneumococcal entry into host cells via Factor H is based on a two-step mechanism. The first and initial contact of Factor H-coated pneumococci is mediated by glycosaminoglycans expressed on the surface of human cells, and the second step, pneumococcal uptake, is integrin-mediated and depends on host signaling molecules such as phosphatidylinositol 3-kinase.