Molecular Pathogenesis of enterotoxigenic E. coli associated enteropathy

项目摘要/摘要 这项工作主要关注产肠毒素大肠杆菌(ETEC)，它是全球最常见的致病细菌 严重的腹泻病。最初在50多年前被确定为严重腹泻疾病的原因 临床表现与霍乱难以区分的患者，ETEC继续威胁着许多人的生命 世界贫困地区的儿童，那里的卫生设施和清洁水仍然有限。而死于 中低收入国家的腹泻病有所下降，这主要是由于口服补液剂的使用。 尽管如此，与这些疾病相关的巨大发病率仍然完全没有得到控制。ETEC是 与一种称为环境肠病或环境肠道功能障碍(EED)的疾病密切相关 营养不良、发育迟缓和智力障碍的后遗症使情况变得更加复杂，掠夺穷人 那些急需人力资本的国家。营养不良的儿童患癌症的风险也大大增加。 死于感染性腹泻、肺炎和其他常见感染。此外，ETEC还与 一种有数百年历史的神秘疾病，被称为热带斯普林斯，通常被诊断为患有 大量反复接触这些病原体。与EED一样，它有营养吸收不良的特点， 消瘦，小肠形态改变。 关于急性腹泻病的分子发病机制，人们知道很多，有热不稳定(LT)和热不稳定(LT)。 稳定(ST)毒素分别通过cAMP和cGMP第二信使通路发出信号，以改变 促进盐和水净流出到肠腔的肠细胞离子通道。然而， 肠道病理性改变和相关后遗症的生物学基础非常差。 明白了。我们最近的研究表明，ETEC毒素破坏了细胞信息，这些信息对 负责营养吸收的小肠表面的维持、生物发生和功能。 因此，目前的项目将处理以下问题： ·“ETEC及其个别毒素对小肠的吸收结构有何影响？” ·“ETEC反复感染如何影响指导其形成的基因的整体表达 营养吸收所需的表面？“ ·“我们能通过中和毒素疫苗来缓解这些影响吗？” 解决这些根本问题将填补我们对ETEC后遗症理解的重要空白 感染，阐明疾病分子发病机制的重要特征，并提供应对策略 预防威胁全世界数百万弱势儿童的疾病。

Project Summary/Abstract This work focuses on enterotoxigenic Escherichia coli (ETEC), globally the most common bacterial cause of serious diarrheal illness. Originally identified more than 50 years ago as a cause of severe diarrheal illness in patients with clinical presentations indistinguishable from cholera, ETEC continue to threaten the lives of many children in poor regions of the world where sanitation and clean water remain limited. While deaths from diarrheal illness in low-middle income countries have declined, largely due to deployment of oral rehydration therapy, the tremendous morbidity associated with these illnesses remains completely unchecked. ETEC are closely linked to a condition known as environmental enteropathy or environmental enteric dysfunction (EED) that is complicated by sequelae of malnutrition, stunted growth, and intellectual impairment, robbing poor countries of badly needed human capital. Children with malnutrition are also at tremendously increased risk of dying from infectious diarrhea, pneumonia, and other common infections. In addition, ETEC have been linked to a centuries-old enigmatic disease, known as tropical sprue, that is typically diagnosed in adults with substantial repeated exposure to these pathogens. With EED it shares features of poor nutrient absorption, wasting, and alterations of small intestinal morphology. Much is known about of the molecular pathogenesis of acute diarrheal disease, with heat- labile (LT) and heat- stable (ST) toxins signaling through cAMP and cGMP second messenger pathways, respectively, to alter enterocyte ion channels that promote the net efflux of salt and water into the intestinal lumen. However, the biology underlying enteropathic changes to the small intestine and related sequelae are very poorly understood. Our recent studies indicate that ETEC toxins compromise cellular messages critical to the maintenance, biogenesis and function of small intestinal surfaces responsible for nutrient absorption. The current project will therefore address the following questions: · “What is the impact of ETEC and its individual toxins on the absorptive architecture of small intestine?” · “How does repeated ETEC infection affect the overall expression of genes that direct formation of surfaces needed for nutrient absorption?” · “Can we mitigate these effects by toxin-neutralizing vaccination?” Addressing these fundamental questions will fill important gaps in our understanding of the sequelae to ETEC infections, elucidate important features of the molecular pathogenesis of disease, and inform strategies to prevent illnesses that threaten millions of disadvantaged children worldwide.