Molecular Pathogenesis of Enterotoxigenic Escherichia coli Infections

描述(由申请人提供)： 产肠毒素大肠杆菌(ETEC)是一种遗传多样性的致病性大肠杆菌，在全球范围内引起数量惊人的腹泻病例，并已成为美国大规模腹泻暴发的原因之一。这些微生物都有能力产生、分泌和向肠道衬里细胞输送耐热(ST)和/或易热(LT)毒素，最终导致腹泻，腹泻可能是严重的霍乱样疾病。在40多年前发现这些产生毒素的大肠杆菌后不久，就识别出了编码在质粒上的毒素基因。直到最近，大多数关于ETEC的研究都集中在少数分子上，即毒素本身和质粒编码的指状定植因子(CFs)。不幸的是，仅以这些抗原为中心的疫苗开发已被证明是非常具有挑战性的，部分原因是CF分子的异质性，以及毒素似乎不能提供对疾病的完全保护(在LT的情况下)，或不具有免疫原性(如ST的情况)。最近几种含有这些抗原的疫苗的失败促使人们寻找替代策略，并回归基础发病机制研究，以解决我们对这些全球重要病原体如何致病的理解差距。虽然人们对这些毒素进入宿主细胞后的分子作用知之甚少，但对细菌如何有效地将这些毒素运送到它们各自的细胞表面受体的了解却很少。这些研究将使用最近开发的分子工具，利用最近发现的新试剂，并利用最先进的方法学来定义ETEC表面上促进这些毒素有效传递的新型分子的卷曲。这些研究的长期目标是将这些信息转化为安全、有效和广泛保护的ETEC疫苗的合理设计。

DESCRIPTION (provided by applicant): The enterotoxigenic Escherichia coli (ETEC) are a genetically diverse type of pathogenic E. coli that cause astounding numbers of cases of diarrheal illness worldwide, and have emerged as a cause of large-scale outbreaks of diarrhea in the United States. These organisms share the ability to produce, secrete, and deliver heat-stable (ST) and/or heat-liable (LT) toxins to the intestinal lining cells ultimately causing diarrhea, which can be severe and cholera-like. The toxin genes encoded on plasmids, were identified shortly after the discovery of these toxin-producing E. coli more than 40 years ago. Most research on ETEC until very recently focused on a small number of molecules, namely the toxins themselves and plasmid-encoded fingerlike colonization factors (CFs). Unfortunately, vaccine development centered on these antigens alone has proven to be very challenging in part because of the heterogeneity of the CF molecules and the fact that the toxins do not appear to afford complete protection against disease (in the case of LT), or are not immunogenic (as is the case for ST). The recent failure of several vaccines incorporating these antigens has prompted both a search for alternative strategiesand a return to basic pathogenesis studies in order to address gaps in our understanding of how these globally important pathogens cause disease. While much is known about the molecular action of these toxins once they enter host cells, very little is known about how the bacteria effectively deliver these toxins to their respective cell surface receptors. These studies will use recently developed molecular tools, capitalize on recent discoveries of new agents, and exploit the state-of-the-art methodology to define the roll of novel molecules on the surface of ETEC that promote the effective delivery of these toxins. The long-term goal of these studies is to translate this information into rational design of a safe, effective, and broadly protective ETEC vaccine.