Deciphering the mechanism of action of Escherichia coli STb toxin using intestinal epithelial cells

产肠毒素大肠杆菌（ETEC）是造成动物生产中腹泻的主要经济损失的原因。ETEC菌株通过定植因子附着在宿主细胞上产生疾病，然后产生一种或多种可作用于肠道组织的肠毒素。STb是ETEC产生的小分子量热稳定毒素之一。这种毒力因子现在被认为是猪新生儿和断奶后腹泻的主要因素。虽然对STb的研究很多，但与ETEC产生的其他肠毒素（如LT和STa）相比，其作用机制的综合信息很少。结果表明，STb必须内化到靶细胞中才能表达毒性。然而，STb的内化途径尚不清楚。STb被归类为一种细胞滋补毒素；目前公认的解释所观察到的分泌的教条是，离子通道，特别是氯离子，受到刺激，同时抑制钠离子，导致水的渗透损失。此外，上皮细胞之间的离子和水通量是由一种叫做紧密连接的结构调节的，这种结构密封了上皮细胞之间的空间。初步数据表明，STb和其他细菌毒素一样，可以通过打开这些结构并使液体流失来作用于TJs。本研究计划的目标是进一步研究STb内化途径和TJ开放。我们的目的是破译STb毒素的作用机制。对这种具有重要临床意义的肠毒素的作用机制的基本了解，可能有助于制定控制性传播感染引起的腹泻病的预防和/或治疗策略。

Enterotoxigenic Escherichia coli (ETEC) is responsible for major economic losses in animal production resulting from diarrhea. ETEC strains produce disease through attachment to host cells via colonization factors and then elaborate one or more type of enterotoxins that can act on the intestinal tissue. STb is one of the small molecular weight heat-stable toxins produced by ETEC. This virulence factor is now recognized as a major player in neonatal and post-weaning diarrhea in pigs. Although there have been many studies on STb, little comprehensive information is available on its mechanism of action compared to other enterotoxins produced by ETEC (such as LT and STa). It was shown that STb has to be internalized into a target cell to express toxicity. However, the internalization route of STb remains unknown. STb is classified as a cytotonic toxin; currently the accepted dogma to explain the secretion observed is that ion channels, in particular chloride, are stimulated together with an inhibition of sodium ions leading to an osmotic loss of water. Also, ion and water fluxes between epithelial cells are regulated by structures called tight junctions that seal the space between them. Preliminary data demonstrated that STb, as was shown also for other bacterial toxins, could act on TJs by opening these structures and permitting a loss of fluid. The goal of the research program is to study further the STb internalization pathway and TJ opening. We aim to decipher the mechanism of action of STb toxin. Fundamental understanding of the mechanism of action of this clinically important enterotoxin has potential for the development of preventive and/or therapeutic strategies to control STb-induced diarrheal disease.