Host iron availability in the pathogenesis of enteropathogenic Yersinia

肠道病原性耶尔森菌发病机制中宿主铁的可用性

基本信息

批准号：
8416931
负责人：
Victoria Auerbuch Stone
金额：
$ 18.37万
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：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416931
关键词：
Affect Alleles American Animal Model Automobile Driving Bacterial Genes Bacterial Infections Bioavailable Biogenesis Collaborations Cysteine Data Defect Disease Escherichia coli European Gene Expression Gene Expression Profile General Population Genes Genetic Transcription Growth Hereditary Disease Hereditary hemochromatosis Homeostasis Hormones Human Immune system Individual Infection Inflammation Inflammation Mediators Inflammatory Interleukin-6 Iron Iron Overload Knowledge Lead Left Letters Liver Mammals Measures Messenger RNA Metals Microbial Biofilms Modeling Mus Mutation Nutrient Organ Oxidative Stress Pasteurella pseudotuberculosis Pathogenesis Patients Plague Predisposition Production Proteins RNA Reaction Recycling Regulon Reporting Research Role Serum Signal Transduction Sulfur Symptoms Testing Tissues Toxicology Type III Secretion System Pathway United States Universities Virulence Yersinia Yersinia enterocolitica Yersinia infections Yersinia pestis cytokine extracellular foodborne pathogen genome sequencing hepcidin human disease immune function macrophage microbial mouse model mutant novel pathogen research study response tool transcription factor transcriptome sequencing transcriptomics uptake

项目摘要

DESCRIPTION (provided by applicant): People with iron overload disorders are more susceptible to serious infections with Yersinia and other bacterial pathogens, yet how and why the course of infection differs in these individuals remains unclear. Mutations that predispose humans to one such iron overload disorder, hereditary hemochromatosis, are very common. One hereditary hemochromatosis-associated mutation in the High Iron Fe gene (Hfe-C282Y) is found in 10% of people of Northern European descent. People with hereditary hemochromatosis accumulate iron in their livers and other tissues, which can lead to increased oxidative stress and organ damage if left untreated. However, hereditary hemochromatosis is also associated with low macrophage iron and immune system defects. Several excellent mouse models of hereditary hemochromatosis exist that recapitulate many symptoms of the human disease. However, these models have been underutilized in terms of characterizing susceptibility to infection. We have identified a gene in the foodborne pathogen Yersinia pseudotuberculosis that controls expression of the type III secretion system (T3SS), a specialized apparatus required by all pathogenic Yersinia to cause disease. This gene has significant homology to the E. coli transcription factor IscR, whose activity is controlled by iron availability and oxidative stress, both of which are abnormal in hereditary hemochromatosis. We hypothesize that IscR is important for proper control of T3SS expression and virulence of Y. pseudotuberculosis and the related pathogen Y. enterocolitica in healthy and iron overloaded hosts. In Aim 1, we will determine the susceptibility of two distinct hereditary hemochromatosis mouse models to infection with Y. pseudotuberculosis and Y. enterocolitica, correlating bacterial replication with tissue iron content and production of inflammatory mediators. In Aim 2, we will determine the Y. pseudotuberculosis protein and RNA genes controlled by changes in iron availability as well as genes controlled by IscR. In addition, the impact of IscR on Y. pseudotuberculosis virulence in healthy and iron overloaded hosts will be determined using the hereditary hemochromatosis mouse models. At the conclusion of this study, we will have established several parameters controlling Yersinia infection in iron overloaded hosts, determined the identity of important Yersinia genes controlled by changes in iron availability, completed initial characterization of th previously-unstudied Yersinia IscR gene, and developed important new tools for further investigating Yersinia pathogenesis and iron overload.

描述（由申请人提供）：铁超负荷疾病的患者更容易受到耶尔森氏菌和其他细菌病原体的严重感染，但是这些人的感染过程如何以及为什么这些人尚不清楚。使人类易受这种铁超载障碍（遗传性血色素肿瘤病）的突变非常普遍。在北欧下降的10％的人中，发现了高铁Fe基因（HFE-C282Y）中与遗传性血色素症相关的突变。遗传性血色素肿瘤病的人会在肝脏和其他组织中积聚铁，如果未治疗，可能会导致氧化应激和器官损伤增加。然而，遗传性血色素沉着症也与低巨噬细胞和免疫系统缺陷有关。存在几种出色的遗传性血色素沉着症小鼠模型，这些模型概括了人类疾病的许多症状。但是，这些模型在表征感染的易感性方面未被充分利用。我们已经确定了pseudotuberculcolosis的食源性病原体中的基因，该基因控制了III型分泌系统（T3SS）的表达，这是所有致病性耶尔森氏菌所要求的一种专门的设备，以引起疾病。该基因与大肠杆菌转录因子ISCR具有重要的同源性，其活性受铁的可用性和氧化应激控制，这两者在遗传性血色素沉着症中均异常。我们假设ISCR对于健康和铁超载宿主中Y. pseudotuberculosis的T3SS表达和Y.肠结肠炎病原体Y. y.肠结肠炎的相关病原体的毒力至关重要。在AIM 1中，我们将确定两种不同的遗传性血色素瘤小鼠模型对Y. pseudotuberculcolisos和Y.肠结肠膜菌感染感染的敏感性，将细菌复制与组织铁含量和产生炎症介体相关联。在AIM 2中，我们将确定由铁的可用性变化以及由ISCR控制的基因控制的Y. y. pseudotubolculosis蛋白和RNA基因。另外，使用遗传性血色素沉着小鼠模型确定ISCR对健康和铁超载宿主中的假结核病毒力的影响。在这项研究的结论中，我们将建立几个控制铁超载宿主中耶尔森氏菌感染的参数，确定了由铁可用性变化控制的重要耶尔西尼亚基因的身份，完成了先前未研究的Yersinia ISCR基因的初始特征，并开发了重要的新工具，以进一步研究Yersinia ia ia andiaia yersinia yernia exprentolos。