Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO 63110.
Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO 63110.
Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):29055-29062. doi: 10.1073/pnas.2012480117. Epub 2020 Nov 2.
The enterotoxigenic (ETEC) are among the most common causes of diarrheal illness and death due to diarrhea among young children in low-/middle-income countries (LMICs). ETEC have also been associated with important sequelae including malnutrition and stunting, placing children at further risk of death from diarrhea and other infections. Our understanding of the molecular pathogenesis of acute diarrheal disease as well as the sequelae linked to ETEC are still evolving. It has long been known that ETEC heat-labile toxin (LT) activates production of cAMP in the cell, signaling the modulation of cellular ion channels that results in a net efflux of salt and water into the intestinal lumen, culminating in watery diarrhea. However, as LT also promotes ETEC adhesion to intestinal epithelial cells, we postulated that increases in cAMP, a critical cellular "second messenger," may be linked to changes in cellular architecture that favor pathogen-host interactions. Indeed, here we show that ETEC use LT to up-regulate carcinoembryonic antigenrelated cell adhesion molecules (CEACAMs) on the surface of small intestinal epithelia, where they serve as critical bacterial receptors. Moreover, we show that bacteria are specifically recruited to areas of CEACAM expression, in particular CEACAM6, and that deletion of this CEACAM abrogates both bacterial adhesion and toxin delivery. Collectively, these results provide a paradigm for the molecular pathogenesis of ETEC in which the bacteria use toxin to drive up-regulation of cellular targets that enhances subsequent pathogen-host interactions.
产肠毒性大肠杆菌（ETEC）是导致低收入和中等收入国家（LMICs）儿童腹泻和死亡的最常见原因之一。ETEC 也与重要的后遗症有关，包括营养不良和发育迟缓，使儿童面临更高的死于腹泻和其他感染的风险。我们对急性腹泻病的分子发病机制以及与 ETEC 相关的后遗症的理解仍在不断发展。长期以来，人们一直知道 ETEC 的不耐热毒素（LT）会激活细胞中的 cAMP 产生，从而信号调节细胞离子通道，导致盐和水净流出肠道腔，最终导致水样腹泻。然而，由于 LT 也促进 ETEC 与肠道上皮细胞的粘附，我们假设细胞内的“第二信使”cAMP 的增加可能与有利于病原体与宿主相互作用的细胞结构变化有关。事实上，在这里我们表明，ETEC 使用 LT 在上皮细胞表面上调癌胚抗原相关细胞粘附分子（CEACAMs），在那里它们作为关键的细菌受体。此外，我们还表明，细菌被特异性募集到 CEACAM 表达区域，特别是 CEACAM6，并且删除这种 CEACAM 会破坏细菌粘附和毒素传递。总之，这些结果为 ETEC 的分子发病机制提供了一个范例，其中细菌利用毒素来驱动细胞靶标的上调，从而增强随后的病原体与宿主的相互作用。
