Division of Infectious Diseases, Department of Medicine, Washington University in Saint Louis, School of Medicine, Saint Louis, MO 63110.
Institute of Anatomy, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany.
Proc Natl Acad Sci U S A. 2024 Sep 17;121(38):e2410679121. doi: 10.1073/pnas.2410679121. Epub 2024 Sep 12.
Enterotoxigenic (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.
肠产毒性大肠杆菌（ETEC）每年导致数亿例腹泻病，从轻症病例到严重的、危及生命的霍乱样腹泻不等。尽管 ETEC 与长期后遗症有关，包括营养不良，但急性腹泻病在很大程度上是自限性的。最近的研究表明，除了引起腹泻外，ETEC 不耐热毒素（LT）还调节肠道上皮细胞中许多基因的表达，包括 ETEC 利用作为受体的癌胚细胞粘附分子（CEACAMs），从而使毒素能够传递。然而，在这里，我们证明 LT 还增强了肠道上皮细胞释放的细胞外囊泡（EV）上 CEACAMs 的表达，并且在人类感染期间，CEACAM 负载的 EV 大量增加，减轻了病原体与宿主的相互作用，清除了游离的 ETEC 毒素，并加速了 ETEC 从胃肠道的清除。总的来说，这些发现表明 CEACAMs 在 ETEC 病原体-宿主相互作用中发挥了多方面的作用，暂时有利于病原体，但最终有助于消除这些常见感染的先天反应。
