Ca2+-dependent repair of pneumolysin pores: A new paradigm for host cellular defense against bacterial pore-forming toxins
Ca2+-dependent repair of pneumolysin pores: A new paradigm for host cellular defense against bacterial pore-forming toxins
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DOI：
10.1016/j.bbamcr.2014.09.005
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发表时间：
2015-09-01
影响因子：
5.1
通讯作者：
Babiychuk, Eduard B.
中科院分区：
文献类型：
--
作者：
Wolfmeier, Heidi;Schoenauer, Roman;Babiychuk, Eduard B.
肺炎链球菌溶血素（Streptococcus pneumoniae，Pneumoniae）是肺炎链球菌的一种重要毒力因子，能通过形成大的跨膜孔使真核细胞通透。在真核细胞上，细胞内存在着多种多样的、常常相互排斥的作用，令人费解。而细胞毒性的PLY可以直接归因于孔介导的影响，机制是负责的PLY诱导的激活宿主cells知之甚少。我们表明，PLY孔可以修复，从而可以防止PLY诱导的细胞死亡。孔诱导的Ca2+从细胞外环境的进入是至关重要的质膜修复的启动。然而，在质膜修复的执行阶段，防止过度的Ca 2+升高的活性Ca 2+螯合也是同样重要的，质膜修复的功效不仅决定了靶细胞的命运，而且还决定了PLY诱导的Ca 2+信号在细胞中的强度、持续时间和重复性，所述细胞在细胞攻击后能够存活。由孔形成和其消除的组合作用引起的细胞内Ca2+动力学模拟受体介导的Ca2+信号传导的模式，其负责激活宿主免疫应答。因此，我们假设质膜修复的pneumpores可能会引起细胞的反应，是类似于目前归因于受体介导的pneumoniaeffects.Our数据提供了新的见解，了解细胞的非免疫防御反应的复杂性，主要的肺炎球菌毒素，在建立和发展中起着至关重要的作用，危及生命的疾病。促进宿主细胞质膜修复及其代谢适应性的疗法可能被证明对肺炎球菌感染的治疗有益。这篇文章是题为：第13届欧洲钙研讨会特刊的一部分。(C)2014爱思唯尔有限公司版权所有。
Pneumolysin (PLY), a key virulence factor of Streptococcus pneumoniae, permeabilizes eukaryotic cells by forming large trans-membrane pores. PLY imposes a puzzling multitude of diverse, often mutually excluding actions on eukaryotic cells. Whereas cytotoxicity of PLY can be directly attributed to the pore-mediated effects, mechanisms that are responsible for the PLY-induced activation of host cells are poorly understood.We show that PLY pores can be repaired and thereby PLY-induced cell death can be prevented. Pore-induced Ca2+ entry from the extracellular milieu is of paramount importance for the initiation of plasmalemmal repair. Nevertheless, active Ca2+ sequestration that prevents excessive Ca2+ elevation during the execution phase of plasmalemmal repair is of no less importance.The efficacy of plasmalemmal repair does not only define the fate of targeted cells but also intensity, duration and repetitiveness of PLY-induced Ca2+ signals in cells that were able to survive after PLY attack. Intracellular Ca2+ dynamics evoked by the combined action of pore formation and their elimination mimic the pattern of receptor-mediated Ca2+ signaling, which is responsible for the activation of host immune responses. Therefore, we postulate that plasmalemmal repair of PLY pores might provoke cellular responses that are similar to those currently ascribed to the receptor-mediated PLY effects.Our data provide new insights into the understanding of the complexity of cellular non-immune defense responses to a major pneumococcal toxin that plays a critical role in the establishment and the progression of life-threatening diseases. Therapies boosting plasmalemmal repair of host cells and their metabolic fitness might prove beneficial for the treatment of pneumococcal infections. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. (C) 2014 Elsevier B.V. All rights reserved.