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：
9913985
负责人：
Victoria Auerbuch Stone
金额：
$ 49.19万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913985
关键词：
Address Affect Alleles Bacteria Binding Sites Biogenesis Blood Blood-Borne Pathogens Cells ChIP-seq Data Defect Development Disease Distant Ectopic Expression Environment Escherichia coli Gene Expression Genes Genetic Transcription Genomic approach Growth Heme Hemin Hereditary hemochromatosis Homeostasis Human Impairment 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 Pathogenicity Pathway interactions Phase Plague Play Population Process Production Proteins Pseudomonas aeruginosa 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 enteric pathogen environmental change foodborne infection genetic regulatory protein heme a human pathogen in vivo iron metabolism mutant novel pathogen pathogenic bacteria 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必需的营养素，哺乳动物宿主已经进化隔离铁并限制入侵微生物的生长的机制数量。但是，细菌有转弯，进化了无数的铁吸收策略以及调节性蛋白质，这些蛋白质感知铁水平以控制铁采集系统和其他对毒力至关重要的基因的表达。铁是鼠疫耶尔西尼亚鼠疫的发病机理和肠病毒Y.肠结肠炎和Y。假结核病。我们最近表明，Y. pseudotuberculosis使用铁硫簇协调称为ISCR的转录因子驱动其主要毒力因子的表达，即YSC III型分泌系统（T3SS），并且ISCR是正确表达许多其他代谢和毒力所必需的基因。我们的初步数据表明，Y. pseudotuberculosis毒力需要ISCR，并在血。由于ISCR是一种全局的转录调节器，因此必须精确确定哪个ISCR调节至关重要途径对于病原体生长和体内生存至关重要。为了解决这个问题，在AIM 1中，我们将确定 Y. pseudotuberculosis中的ISCR调节，它如何受铁的影响，并评估其在Y中的保护。 Pestis和Y. Enterocolitica。此外，在AIM 2中，我们将测试ISCR对YSC T3SS的控制如何影响Y。正常小鼠和铁超载小鼠的假结核病毒力。最后，在AIM 3中，我们将确定ISCR如何使Y.假结核病在血液中的存活以及这如何影响传播感染。在结论这项研究，我们将建立ISCR控制的途径，并确定它们如何促进发病机理。这项工作将有助于阐明病原体感知他们的方式在感染过程中优化毒力因子利用的环境。