Potent diarrheagenic mechanism mediated by the cooperative action of three enteropathogenic Escherichia coli-injected effector proteins

被引:87
作者
Dean, P
Maresca, M
Schüller, S
Phillips, AD
Kenny, B
机构
[1] Univ Newcastle, Sch Med, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[2] Royal Free Hosp, Ctr Paediat Gastroenterol, London NW3 2PF, England
[3] Univ Coll Med Sch, London NW3 2PF, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
Caco-2; diarrhea; effacement; SGLT-1;
D O I
10.1073/pnas.0509451103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Enteropathogenic Escherichia coli (EPEC) induces a severe watery diarrhea responsible for several hundred thousand infant deaths each year by a process correlated with the loss (effacement) of absorptive microvilli. Effacement is linked to the locus of enterocyte effacement pathogenicity island that encodes an "injection system," "effector" proteins, and the Intimin outer membrane protein. Here, we reveal that effacement (i) is a two-step process, (ii) requires the cooperative action of three injected effectors (Map, EspF, and Tir) as well as Intimin, and (iii) leads to the retention, not release (into the extracellular milieu), of the detached microvillar material. We also discover that EPEC rapidly inactivates the sodium-D-glucose cotransporter (SGLT-1) by multiple mechanisms. Indeed, the finding that one mechanism occurs more rapidly than microvilli effacement provides a plausible explanation for the rapid onset of severe watery diarrhea, given the crucial role of SGLT-1 in the daily uptake of approximate to 6 liters of fluids from the normal intestine. The importance of SGLT-1 in the disease process is supported by severe EPEC diarrheal cases being refractory to oral rehydration therapy (dependent on SGLT-1 function). Moreover, the identification of effector activities that alter microvilli structure and SGLT-1 function provides new tools for studying the underlying regulatory processes.
引用
收藏
页码:1876 / 1881
页数:6
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