Host iron availability in the pathogenesis of enteropathogenic Yersinia

描述（由申请人提供）：患有铁超载疾病的人更容易受到耶尔森氏菌和其他细菌病原体的严重感染，但这些个体的感染过程如何以及为什么不同仍不清楚。使人类易患这种铁超载疾病的突变，遗传性血色素沉着症，是非常常见的。在10%的北欧后裔中发现了一种与血色素沉着症相关的遗传性高铁基因（Hfe-C282Y）突变。遗传性血色素沉着症患者在肝脏和其他组织中积累铁，如果不及时治疗，会导致氧化应激增加和器官损伤。然而，遗传性血色素沉着症也与巨噬细胞铁含量低和免疫系统缺陷有关。存在几种优秀的遗传性血色素沉着症小鼠模型，再现了人类疾病的许多症状。然而，这些模型在表征感染易感性方面尚未得到充分利用。我们已经在食源性病原体假结核耶尔森菌中发现了一个基因，该基因控制III型分泌系统（T3SS）的表达，这是所有致病性耶尔森菌引起疾病所需的专门装置。该基因与大肠杆菌转录因子IscR具有显著的同源性，其活性受铁可用性和氧化应激控制，这两者在遗传性血色素沉着症中都是异常的。我们推测，在健康和铁负荷过重的宿主中，IscR对于适当控制T3SS表达和假结核耶氏菌及相关病原体小肠结肠炎耶氏菌的毒力很重要。在Aim 1中，我们将确定两种不同的遗传性血色素沉着症小鼠模型对假结核耶氏菌和小肠结肠炎耶氏菌感染的易感性，将细菌复制与组织铁含量和炎症介质的产生联系起来。在Aim 2中，我们将确定由铁可用性变化控制的假结核杆菌蛋白和RNA基因以及由IscR控制的基因。此外，IscR对健康和铁超载宿主的假结核杆菌毒力的影响将通过遗传性血色素沉着小鼠模型来确定。在本研究结束时，我们将建立控制铁超载宿主中耶尔森氏菌感染的几个参数，确定受铁可用性变化控制的重要耶尔森氏菌基因的身份，完成先前未研究的耶尔森氏菌IscR基因的初步表征，并为进一步研究耶尔森氏菌发病机制和铁超载开发重要的新工具。

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.