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，但这些人的感染过程如何以及为什么不同仍不清楚。使人类易患铁超负荷疾病遗传性血色素沉着症的突变非常常见。在10%的北方欧洲血统的人中发现了高铁Fe基因（Hfe-C282 Y）中的一种遗传性血色病相关突变。患有遗传性血色病的人在肝脏和其他组织中积累铁，如果不治疗，会导致氧化应激增加和器官损伤。然而，遗传性血色病也与低巨噬细胞铁和免疫系统缺陷有关。存在几种极好的遗传性血色病小鼠模型，其概括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未得到充分利用。我们已经在食源性病原体假结核耶尔森氏菌中确定了一个基因，该基因控制III型分泌系统（T3 SS）的表达，这是所有致病性耶尔森氏菌引起疾病所需的一种特殊装置。该基因与E.大肠杆菌转录因子IscR，其活性受铁利用率和氧化应激控制，这两者在遗传性血色病中均异常。我们推测IscR对于正确控制T3 SS表达和Y.假结核及相关病原Y.小肠结肠炎在健康和铁超载的主机。在目的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感染Y。pseudotuberculosis和Y.小肠结肠炎，相关的细菌复制与组织铁含量和炎症介质的生产。在目标2中，我们将确定Y。假结核蛋白和RNA基因控制的变化，铁的可用性，以及基因控制的IscR。此外，还研究了IscR对Y.将使用遗传性血色素沉着症小鼠模型确定健康和铁超载宿主中的假结核毒力。在这项研究的结论，我们将建立几个参数控制耶尔森氏菌感染的铁超载主机，确定了重要的耶尔森氏菌基因的身份控制铁的可用性的变化，完成了初步表征th以前未研究的耶尔森氏菌IscR基因，并开发了重要的新工具，进一步研究耶尔森氏菌的发病机制和铁超载。 公共卫生相关性：遗传性血色病是美国最常见的遗传性疾病之一，其中肝脏等器官铁超载。患有遗传性血色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。然而，目前尚不清楚是否增加细菌生长或免疫功能缺陷铁的可用性易患遗传性血色病患者这些严重的感染。该项目调查了遗传性血色病哺乳动物对耶尔森氏菌感染易感性增强的根本原因，并研究了铁可用性的变化如何控制对引起疾病至关重要的耶尔森氏菌基因的表达。

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. PUBLIC HEALTH RELEVANCE: Hereditary hemochromatosis is one of the most common genetic disorders in the United States, in which organs such as the liver become overloaded with iron. People with hereditary hemochromatosis are more susceptible to serious infections with Yersinia as well as other bacterial pathogens. However, it is not clear whether increased iron availability for bacterial growth or defects in immune function predispose patients with hereditary hemochromatosis to these serious infections. This project investigates the underlying causes of enhanced susceptibility to Yersinia infection in mammals with hereditary hemochromatosis and examines how changes in iron availability control expression of Yersinia genes vital for causing disease.