The Role of STa in ETEC Pathogenesis

产肠毒素大肠埃希菌(ETEC)是导致儿童发病和死亡的主要原因之一。 发展中国家。2010年，估计每年因ETEC疾病而死亡的人数为157,000人(9 占所有死亡人数的百分比)，约占28天至5天儿童死亡人数的1% 几年前。发展对ETEC的自然免疫力需要多年的反复感染，这增加了 关于这种有机体是如何阻止免疫发展的问题。ETEC通过以下方式致病 用定植因子抗原定植近端小肠，并通过产生不耐热的 (LT)或耐热性(ST)肠毒素。 当给人类志愿者服用时，它具有高度的免疫原性并诱导自身抗体。另一方面， ST是一种小的非免疫原性多肽。我们最近开始调查ST On的贡献 ETEC的发病机制。我们的初步数据表明：(1)STA1基因(编码Sth)在 厌氧条件，如可以在肠道内发现(2)ST结合铁和铁硫(FES) 在这些厌氧条件下，(3)铁和FeS簇结合的ST从肠道诱导的cGMP较少 (4)ST抑制粪便中抗ETEC的IgA和Th17免疫应答 H10407(全细胞+O78-内毒素)。 根据初步数据，假设(1)STA1在厌氧条件下上调 氧敏感转录调控因子FNR(2)ST能结合铁和FeS簇， 调节其毒性，以及(3)ST抑制粘膜对ETEC抗原的免疫，从而维持 由铁感应介导的宿主对同一生物体反复感染的敏感性。具体的 目标是1)确定调节编码ST的基因转录的环境条件，2) 表征ST的铁和铁-硫团簇结合特性以及这如何控制ST的肠道毒性， 3)确定ST如何改变粘膜对ETEC抗原的免疫应答。 在这些研究的结论中，导致ST表达和分泌增强的生长条件将 将被澄清。此外，还将阐述铁和FeS团簇结合的ST对ST毒性的作用。最后， ST介导的粘膜对ETEC抗原免疫反应的抑制机制将 提供令人信服的证据，说明为什么反复感染ETEC需要多年才能形成自然免疫力。

Enterotoxigenic Escherichia coli (ETEC) is one of the major causes of childhood morbidity and mortality in developing countries. In 2010, annual mortality from illness due to ETEC was estimated at 157,000 deaths (9 percent of all deaths attributed to diarrhea) and approximately 1 percent of all deaths in children 28 days to 5 years of age. Development of natural immunity to ETEC requires years of recurrent infections, which raises the question as to what about this organism prevents the development of immunity. ETEC cause disease by colonizing the proximal small intestine with colonization factor antigens and through production of heat-labile (LT) or heat-stable (ST) enterotoxins. LT is highly immunogenic and induces antibodies to itself when given to human volunteers. On the other hand ST is a small non-immunogenic peptide. We have recently begun to investigate the contribution of ST on ETEC pathogenesis. Our preliminary data indicate (1) sta1 gene (encoding STh) is up-regulated under anaerobic conditions, as could be found within the intestinal tract (2) ST binds both iron and iron-sulfur (FeS) clusters under these anaerobic conditions, (3) iron and FeS cluster bound ST elicits less cGMP from intestinal epithelial cells than native ST, and (4) ST suppresses fecal IgA and Th17 immune responses against ETEC H10407 (whole cell and O78-LPS). Based on the preliminary data, the hypotheses are that (1) sta1 is up-regulated in response to anaerobic conditions by the oxygen-sensitive transcriptional regulator FNR (2) ST can bind iron and FeS clusters, which regulate its toxicity, and (3) ST suppresses mucosal immunity to ETEC antigens thereby maintaining susceptibility of the host to recurrent infections by the same organism mediated by iron sensing. The specific aims are 1) Determine the environmental conditions that regulate transcription of genes encoding ST, 2) Characterize the iron and iron-sulfur cluster binding properties of ST and how this controls ST enterotoxicity, and 3) Determine how ST modifies mucosal immune responses to ETEC antigens. At the conclusion of these studies, growth conditions that result in enhanced ST expression and secretion will be elucidated. In addition, the role of iron and FeS cluster bound ST on ST toxicity will be expounded. Lastly, mechanisms concerning ST-mediated suppression of mucosal immune responses to ETEC antigens will provide compelling evidence for why it takes years of recurrent ETEC infections to develop natural immunity.