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

利用肠上皮细胞破译大肠杆菌 STb 毒素的作用机制

• 批准号: 139070-2013
• 负责人: Dubreuil, Daniel
• 金额: $ 1.82万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=680424
• 关键词: Deciphering; mechanism; action; Escherichia; coli

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.

肠毒素大肠杆菌（ETEC）负责腹泻引起的动物产量的重大经济损失。 ETEC菌株通过结肠化因子附着在宿主细胞上产生疾病，然后详细说明一种或多种可以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。现在，这种毒力因素被认为是猪新生儿和断奶后腹泻的主要参与者。尽管对STB进行了许多研究，但与ETEC产生的其他肠毒素（例如LT和STA）相比，几乎没有有关其作用机理的全面信息。结果表明，必须将STB内部化到靶细胞中以表达毒性。但是，STB的内在化途径仍然未知。 STB被归类为细胞毒素；目前，可以解释观察到的分泌的公认教条是，离子通道，尤其是氯化物，并抑制导致水渗透损失的钠离子。同样，上皮细胞之间的离子和水通量受称为密封它们之间空间的紧密连接结构的调节。初步数据表明，正如其他细菌毒素所示的STB可以通过打开这些结构并允许流体损失对TJ作用。研究计划的目的是进一步研究STB内部化途径和TJ开放。我们旨在破译STB毒素作用机理。对这种临床上重要的肠毒素作用机理的基本理解具有开发预防和/或治疗策略来控制STB诱导的腹泻病的潜力。