Attaching and effacing pathogen-induced tight junction disruption in vivo
Attaching and effacing pathogen-induced tight junction disruption in vivo
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DOI：
10.1111/j.1462-5822.2005.00656.x
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发表时间：
2006-04-01
影响因子：
3.4
通讯作者：
Finlay, BB
中科院分区：
文献类型：
--
作者：
Guttman, JA;Li, YL;Finlay, BB
腹泻是人类附着和消除 (A/E) 病原体、肠出血性大肠杆菌 (EHEC) 和肠致病性大肠杆菌 (EPEC) 感染的标志。尽管这些病原体引起腹泻的机制尚不清楚，但细胞培养结果表明这些病原体可能以紧密连接为目标。结肠中的紧密连接充当物理细胞间屏障，将管腔内容物与上皮的内腔区域分开并防止混合。因此，A/E 病原体对肠上皮紧密连接的破坏可能导致消化道屏障功能丧失；然而，这仍然未经审查。在这里，我们首次证明 A/E 病原体感染会导致自然疾病期间紧密连接的形态改变。紧密连接改变以跨膜紧密连接蛋白 Claudin 1、3 和 5 的重新定位为特征，是一种功能性破坏；分子示踪剂通常不会穿透未感染的上皮，但会穿过病原体感染的上皮。功能性连接破坏伴随着结肠腔水含量的增加而发生。对组织的影响取决于细菌 III 型效应子 EspF（大肠杆菌分泌蛋白 F），因为缺乏 EspF 的细菌虽然能够定殖，但存在连接破坏缺陷，导致与野生型感染相比结肠中水的比例减少。这些结果表明，A/E 病原体引起的腹泻是功能性紧密连接破坏的一部分。
Diarrhoea is a hallmark of infections by the human attaching and effacing (A/E) pathogens, enterohaemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC). Although the mechanisms underlying diarrhoea induced by these pathogens remain unknown, cell culture results have suggested that these pathogens may target tight junctions. Tight junctions in the colon function as physical intercellular barriers that separate and prevent mixing of the luminal contents with adlumenal regions of the epithelium. Consequently, it is thought that the disruption of intestinal epithelial tight junctions by A/E pathogens could result in a loss of barrier function in the alimentary tract; however, this remains unexamined. Here we demonstrate for the first time that A/E pathogen infection results in the morphological alteration of tight junctions during natural disease. Tight junction alteration, characterized by relocalization of the transmembrane tight junction proteins claudin 1, 3 and 5, is a functional disruption; molecular tracers, which do not normally penetrate uninfected epithelia, pass across pathogen-infected epithelia. Functional junction disruption occurs with a concomitant increase in colon luminal water content. The effects on tissue are dependent upon the bacterial type III effector EspF (E. coli secreted protein F), because bacteria lacking EspF, while able to colonize, are defective for junction disruption and result in decreased proportions of water in the colon compared with wild-type infection. These results suggest that the diarrhoea induced by A/E pathogens occurs as part of functional tight junction disruption.