Shiga Toxin Activates Complement and Binds Factor H: Evidence for an Active Role of Complement in Hemolytic Uremic Syndrome
Shiga Toxin Activates Complement and Binds Factor H: Evidence for an Active Role of Complement in Hemolytic Uremic Syndrome
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DOI：
10.4049/jimmunol.0900151
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发表时间：
2009-05-15
影响因子：
4.4
通讯作者：
Wuerzner, Reinhard
中科院分区：
文献类型：
--
作者：
Orth, Dorothea;Khan, Abdul Basit;Wuerzner, Reinhard
肠出血性大肠杆菌（EHEC）感染是溶血性尿毒综合征（HUS）的主要原因。滋贺毒素（Stx），特别是Stx 2，被认为是EHEC的主要毒力因子，有助于HUS的发病。除了EHEC相关的HUS外，还有遗传性非典型形式的HUS，主要由补体调节因子突变引起。本研究的目的是调查是否补体也参与了EHEC诱导的典型HUS的发病机制，通过直接或间接激活其抑制剂的参与。纯化的Stx 2通过旁路途径显著激活补体，并且发现其仅在激活时与因子H（FH）结合。没有明显的裂解或破坏FH是可见的，在流体相的辅因子活性不受影响，但明显延迟表面附着FH，它是必不可少的宿主细胞保护。使用FH构建体的结合研究揭示Stx 2结合短共有重复序列（SCR）6-8和SCR 18 -20，但不结合SCR 16 -17，即，涉及FH的表面识别功能的区域。总之，补体，特别是FH，不仅在非典型HUS中起重要作用，而且很可能在EHEC诱导的HUS中也起重要作用。免疫学杂志，2009，182：6394-6400.
Infections with enterohemorrhagic Escherichia coli (EHEC) are a major cause of hemolytic uremic syndrome (HUS). Shiga toxins (Stxs), especially Stx2, are believed to represent major virulence factors of EHEC, contributing to HUS pathogenesis. Beside EHEC-associated HUS, there are hereditary atypical forms of HUS, which are mostly caused by mutations of complement regulators. The aim of the present study was to investigate whether or not complement is also involved in the pathogenesis of EHEC-induced typical HUS, by being activated either directly or indirectly by involvement of its inhibitors. Purified Stx2 markedly activated complement via the alternative pathway and was found to bind to factor H (FH), however, only when it was active. No apparent cleavage or destruction of FH was visible, and cofactor activity in fluid phase was unaffected, but clearly delayed for surface-attached FH, where it is essential for host cell protection. Binding studies using FH constructs revealed that Stx2 binds to short consensus repeats (SCRs) 6-8 and SCRs18-20, but not to SCRs16-17, i.e., to regions involved in the surface recognition function of FH. In conclusion, complement, and in particular FH, not only plays an important role in atypical HUS, but most probably also in EHEC-induced HUS. The Journal of Immunology, 2009,182: 6394-6400.