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Host iron and Yersinia pathogenesis

宿主铁与耶尔森氏菌发病机制

基本信息

批准号：
9175810
负责人：
Victoria Auerbuch Stone
金额：
$ 48.49万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
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：
2016-05-10 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9175810
关键词：
Address Affect Alleles Bacteria Binding Sites Biogenesis Blood Blood-Borne Pathogens Cells ChIP-seq Data Defect Development Disease Ectopic Expression Environment Escherichia coli Gene Expression Genes Genetic Transcription Genome Genomic approach Growth Heme Heme Iron Hemin Hereditary hemochromatosis Homeostasis Human Infection Inflammation Inflammatory Inflammatory Response Intestines Invaded Investigation Iron Iron Metabolism Disorders Iron Overload Link Metabolic Metals Microbe Modeling Mus Mutate Mutation Nature Nutrient Orthologous Gene Pasteurella pseudotuberculosis Pathogenesis Pathway interactions Phase Plague Play Population Process Production Proteins Pseudomonas Publishing Regulation Regulon Reporter Role Route Shapes Sheep Signal Transduction Site Source Sulfur System Testing Tissue imaging Tissues Type III Secretion System Pathway Vibrio vulnificus Virulence Virulence Factors Work Yersinia Yersinia enterocolitica Yersinia infections Yersinia pestis antimicrobial cytokine environmental change foodborne infection genetic regulatory protein heme a in vivo iron metabolism mutant novel pathogen promoter response transcription factor transcriptome sequencing uptake

项目摘要

The majority of bacterial pathogens require iron as an essential nutrient and mammalian hosts have evolved a number of mechanisms to sequester iron and limit the growth of invading microbes. However, bacteria have, in turn, evolved a myriad of iron uptake strategies as well as regulatory proteins that sense iron levels to control expression of iron acquisition systems and other genes critical for virulence. Iron is an important factor in the pathogenesis of the plague agent Yersinia pestis and the enteropathogens Y. enterocolitica and Y. pseudotuberculosis. We recently showed that Y. pseudotuberculosis uses an iron-sulfur cluster coordinating transcription factor called IscR to drive expression of its major virulence factor, the Ysc type III secretion system (T3SS), and that IscR is required for proper expression of a number of other metabolic and virulence genes. Our preliminary data show that IscR is required for Y. pseudotuberculosis virulence and for survival in blood. As IscR is a global transcriptional regulator, it is critical to determine precisely which IscR-regulated pathways are important for pathogen growth and survival in vivo. To address this, in Aim 1, we will determine the IscR regulon in Y. pseudotuberculosis, how it is influenced by iron levels, and assess its conservation in Y. pestis and Y. enterocolitica. In addition, in Aim 2, we will test how IscR control of the Ysc T3SS impacts Y. pseudotuberculosis virulence in normal and iron overloaded mice. Lastly, in Aim 3, we will determine how IscR enables Y. pseudotuberculosis survival in blood and how this influences disseminated infection. At the conclusion of this study, we will have established the pathways controlled by IscR in Yersinia and determined how they contribute to pathogenesis. This work will help to elucidate the ways in which pathogens sense their environment to optimize virulence factor utilization during infection.

大多数细菌病原体需要铁作为一种基本的营养物质，哺乳动物的宿主已经进化出一种隔离铁和限制入侵微生物生长的机制的数量。然而，细菌已经在反过来，进化出了无数的铁摄取策略以及感知铁水平来控制的调节蛋白铁获取系统和其他毒力关键基因的表达。铁是影响人体健康的重要因素。鼠疫耶尔森氏菌和肠道病原菌小肠结肠炎耶尔森氏菌和耶尔森氏菌的致病机理。假性肺结核。我们最近发现假结核杆菌使用一种铁-硫簇来协调被称为ISCR的转录因子驱动其主要毒力因子YSC III型分泌的表达系统(T3SS)，而ISCR是正确表达许多其他代谢和毒力所必需基因。我们的初步数据表明，ISCR是假结核杆菌致病和存活所必需的。血。由于ISCR是一个全球性的转录调节因子，因此准确地确定ISCR调控的是哪一个是至关重要的途径对于病原体在体内的生长和存活是重要的。为了解决这个问题，在目标1中，我们将确定 ISCR在假结核杆菌中的调控，它如何受铁水平的影响，并评估其在Y。鼠疫和小肠结肠炎耶尔森菌。此外，在目标2中，我们将测试YSC T3SS的ISCR控制对Y。假结核在正常和铁超载小鼠中的毒力。最后，在目标3中，我们将确定国际SCR如何使假结核杆菌在血液中存活，以及这如何影响播散性感染。在本研究的结论是，我们将在耶尔森氏菌中建立ISCR控制的通路，并确定它们在发病机制中的作用。这项工作将有助于阐明病原体如何感知他们的在感染期间优化毒力因子利用的环境。