Bielaszewska Martina, Aldick Thomas, Bauwens Andreas, Karch Helge
Institute of Hygiene, University of Münster, Robert-Koch-Str. 41, 48149 Münster, Germany.
Institute of Hygiene, University of Münster, Robert-Koch-Str. 41, 48149 Münster, Germany.
Int J Med Microbiol. 2014 Jul;304(5-6):521-9. doi: 10.1016/j.ijmm.2014.05.005. Epub 2014 May 15.
Enterohemorrhagic Escherichia coli (EHEC) cause diarrhea, bloody diarrhea and hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy affecting the renal glomeruli, the intestine, and the brain. The pathogenesis of EHEC-mediated diseases is incompletely understood. In addition to Shiga toxins, the major virulence factors of EHEC, the contribution of EHEC hemolysin (EHEC-Hly), also designated EHEC toxin (Ehx), which is a member of the RTX (repeats-in-toxin) family, is increasingly recognized. The toxin and its activation and secretion machinery are encoded by the EHEC-hlyCABD operon, in which EHEC-hlyA is the structural gene for EHEC-Hly and the EHEC-hlyC product mediates post-translational activation of EHEC-Hly; the EHEC-hlyB- and EHEC-hlyD-encoded proteins form, together with genetically unlinked TolC, the type I secretion system that transports EHEC-Hly out of the bacterial cell. EHEC-Hly exists in two biologically active forms: as a free EHEC-Hly, and an EHEC-Hly associated with outer membrane vesicles (OMVs) that are released by EHEC during growth. The OMV-associated form results from a rapid binding of free EHEC-Hly to OMVs upon its extracellular secretion. The OMV association stabilizes EHEC-Hly and thus substantially prolongs its hemolytic activity compared to the free toxin. The two EHEC-Hly forms differ by their mechanism of toxicity toward human intestinal epithelial and microvascular endothelial cells, which are the major targets during EHEC infection. The free EHEC-Hly lyses human microvascular endothelial cells, presumably by pore formation in the cell membrane. In contrast, the OMV-associated EHEC-Hly does not lyse any of these cell types, but after its cellular internalization via OMVs it targets mitochondria and triggers caspase-9-mediated apoptosis. The proinflammatory potential of EHEC-Hly, in particular its ability to elicit secretion of interleukin-1β from human monocytes/macrophages, might be an additional mechanism of its putative contribution to the pathogenesis of EHEC-mediated diseases. Increasing understanding of molecular mechanisms underlying interaction of EHEC-Hly with target cells as well as the host cell responses to the toxin supports the involvement of EHEC-Hly in the pathogenesis of EHEC-mediated diseases and forms a basis for prevention of the EHEC-Hly-mediated injury during human infection.
肠出血性大肠杆菌（EHEC）可导致腹泻、血性腹泻和溶血尿毒综合征（HUS），这是一种影响肾小球、肠道和大脑的血栓性微血管病。EHEC介导疾病的发病机制尚未完全明了。除了EHEC的主要毒力因子志贺毒素外，EHEC溶血素（EHEC-Hly）（也称为EHEC毒素（Ehx），它是RTX（毒素重复序列）家族的成员）的作用也越来越受到认可。该毒素及其激活和分泌机制由EHEC-hlyCABD操纵子编码，其中EHEC-hlyA是EHEC-Hly的结构基因，EHEC-hlyC产物介导EHEC-Hly的翻译后激活；EHEC-hlyB和EHEC-hlyD编码的蛋白与基因上不相关的TolC一起形成将EHEC-Hly转运出细菌细胞的Ⅰ型分泌系统。EHEC-Hly以两种生物活性形式存在：一种是游离的EHEC-Hly，另一种是与EHEC在生长过程中释放的外膜囊泡（OMV）相关的EHEC-Hly。与OMV相关的形式是游离的EHEC-Hly在细胞外分泌后迅速与OMV结合的结果。与OMV结合可使EHEC-Hly稳定，因此与游离毒素相比，其溶血活性大大延长。这两种EHEC-Hly形式对人肠道上皮细胞和微血管内皮细胞（EHEC感染期间的主要靶细胞）的毒性机制不同。游离的EHEC-Hly可裂解人微血管内皮细胞，可能是通过在细胞膜上形成孔道。相比之下，与OMV相关的EHEC-Hly不会裂解任何这些细胞类型，但在通过OMV被细胞内化后，它靶向线粒体并触发caspase-9介导的细胞凋亡。EHEC-Hly的促炎潜力，特别是其从人单核细胞/巨噬细胞中诱导白细胞介素-1β分泌的能力，可能是其对EHEC介导疾病发病机制的假定贡献的另一种机制。对EHEC-Hly与靶细胞相互作用的分子机制以及宿主细胞对该毒素反应的深入了解支持EHEC-Hly参与EHEC介导疾病的发病机制，并为预防人类感染期间EHEC-Hly介导的损伤奠定了基础。
