Abstract:
Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of diarrheal illnesses annually ranging from mildly symptomatic cases to severe, life-threatening cholera-like diarrhea. Although ETEC are associated with long-term sequelae including malnutrition, the acute diarrheal illness is largely self-limited. Recent studies indicate that in addition to causing diarrhea, the ETEC heat-labile toxin (LT) modulates the expression of many genes in intestinal epithelia, including carcinoembryonic cell adhesion molecules (CEACAMs) which ETEC exploit as receptors, enabling toxin delivery. Here however, we demonstrate that LT also enhances the expression of CEACAMs on extracellular vesicles (EV) shed by intestinal epithelia and that CEACAM-laden EV increase in abundance during human infections, mitigate pathogen-host interactions, scavenge free ETEC toxins, and accelerate ETEC clearance from the gastrointestinal tract. Collectively, these findings indicate that CEACAMs play a multifaceted role in ETEC pathogen-host interactions, transiently favoring the pathogen, but ultimately contributing to innate responses that extinguish these common infections.
摘要:
产肠毒素大肠杆菌(ETEC)每年导致数以亿计的腹泻疾病,从轻度症状到严重,威胁生命的霍乱样腹泻.尽管ETEC与包括营养不良在内的长期后遗症有关,急性腹泻病很大程度上是自限性的。最近的研究表明,除了引起腹泻,ETEC不耐热毒素(LT)调节肠上皮细胞中许多基因的表达,包括ETEC用作受体的癌胚细胞粘附分子(CEACAM),使毒素递送成为可能。然而,在这里,我们证明,LT还增强了CEACAM在肠上皮脱落的细胞外囊泡(EV)上的表达,并且在人类感染期间,载有CEACAM的EV丰度增加,减轻病原体-宿主相互作用,清除游离的ETEC毒素,并加速从胃肠道中清除ETEC。总的来说,这些发现表明CEACAM在ETEC病原体-宿主相互作用中起着多方面的作用,暂时偏爱病原体,但最终导致先天反应,消灭这些常见的感染。
■产肠毒素大肠杆菌,其特征在于产生热不稳定(LT)和热稳定(ST)毒素,是低收入地区腹泻的常见原因,每年导致数亿人感染,以及前往流行地区的旅行者腹泻的主要原因。虽然这些感染可能很严重,类似霍乱,他们通常是自我限制的。这些研究表明,宿主肠道细胞产生的细胞外囊泡可以在细胞表面一定距离处捕获细菌及其分泌的毒素,可能充当分子诱饵以中和肠毒素并消灭感染。