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The Role of STa in ETEC Pathogenesis

STa 在 ETEC 发病机制中的作用

基本信息

批准号：
9320323
负责人：
Jacob P. Bitoun
金额：
$ 37.63万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-10 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320323
关键词：
1 year old 5 year old ADP ribosylation Adenylate Cyclase Antibodies Antigen Targeting Antigens Binding Binding Sites Biochemical Cells Cessation of life Child Childhood Chloride Ion Chlorides Cyclic AMP Cyclic GMP Cystic Fibrosis Transmembrane Conductance Regulator Data Developing Countries Development Diarrhea Disease EMSA Enterotoxins Environment Epithelial Cells Escherichia coli Infections Exposure to Family suidae Future Genes Genetic Transcription Goals Growth Guanylate Cyclase Heating Human Volunteers IL8 gene Immune response Immunity Immunoglobulin A Immunologics In Situ In Vitro Infection Interleukin-6 Intestines Iron Lead Licensing Mediating Memory Modeling Morbidity - disease rate Mucosal Immune Responses Mucosal Immunity Natural Immunity Operon Oral Organism Oxygen Pathogenesis Peptides Phosphorylation Physiological Predisposition Property Proteins Recurrence Recurrent disease Role Severities Signal Transduction Small Intestines Sulfur Surface Therapeutic Thermogenesis Toxic effect Toxin Vaccination Vaccines Virulence Factors Water adaptive immunity base colonization factor antigens combat enterotoxigenic Escherichia coli immunogenic improved insight mortality mouse model novel strategies prevent promoter receptor response

项目摘要

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.

产肠毒素大肠杆菌（ETEC）是儿童发病和死亡的主要原因之一，发展中国家2010年，估计每年有157，000人死于ETEC（9 腹泻导致的死亡占所有死亡的1%），28天至5岁儿童死亡的约1% 岁的对ETEC的天然免疫力的发展需要多年的反复感染，这提高了ETEC的免疫力。问题是，这种生物体是如何阻止免疫力的发展的。ETEC通过以下方式致病：用定殖因子抗原定殖近端小肠，并通过产生热不稳定的 (LT)或热稳定（ST）肠毒素。 LT具有高度免疫原性，当给予人类志愿者时，可诱导自身抗体。另一方面 ST是一种小的非免疫原性肽。我们最近开始研究ST对 ETEC发病机制。我们的初步数据表明：（1）sta 1基因（编码STh）在厌氧条件下，可以在肠道内发现（2）ST结合铁和铁硫（FeS）（3）铁和FeS簇结合ST，不释放肠源性cGMP ST抑制粪便伊加和Th 17对ETEC的免疫应答 H10407（全细胞和O 78-LPS）。基于初步的数据，我们假设：（1）sta 1在厌氧条件下表达上调，氧敏感转录调节因子FNR（2）ST的条件下可以结合铁和FeS簇，调节其毒性，和（3）ST抑制对ETEC抗原的粘膜免疫，从而维持宿主对由铁感应介导的相同生物体的反复感染的易感性。具体目的是1）确定调节编码ST的基因的转录的环境条件，2）表征ST的铁和铁硫簇结合特性，以及这如何控制ST的肠毒性，和3）确定ST如何改变对ETEC抗原的粘膜免疫应答。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被阐明。此外，铁和FeS簇结合ST的作用ST毒性将阐述。最后，关于ST介导的对ETEC抗原的粘膜免疫应答抑制的机制将提供了令人信服的证据，说明为什么ETEC反复感染需要数年才能产生天然免疫力。