The Contribution of Intracellular Heme Trafficking to Staphylococcal Pathogenesis

描述(由申请人提供)：金黄色葡萄球菌是美国发病率和死亡率的重要原因。由于从医院和社区分离的抗药性菌株数量不断增加，这种病原体是一个主要问题。感染金黄色葡萄球菌会在所有主要器官引起严重的炎症反应。像大多数病原体一样，金黄色葡萄球菌的生长需要铁，而感染期间首选的铁源是血红素。在获得血红素后，葡萄球菌血红素降解酶催化释放游离铁。血红素也可以优先分离到膜上，完好无损，可能用作膜辅助因子。这表明金黄色葡萄球菌根据其代谢需要不同地利用血红素。自相矛盾的是，许多获得血红素的病原体也可以合成新的血红素。目前尚不清楚血红素的获得和合成在细胞内是如何协调的。根据我们的初步数据，我们假设血红素是根据它是外源性获得的还是内源性合成的而进行差异排序的。这项应用建议通过确定质膜中血红素的分子接受者来检验这一假说。这些研究将大大增加我们对葡萄球菌血红素运输和呼吸的了解，并可能导致新的治疗靶点的确定。这项应用的具体目的是：目的1.确定外源性获得的血红素在葡萄球菌中的细胞内命运。目的2.明确内源性血红素在葡萄球菌感染过程中的生理作用。 公共卫生相关性：金黄色葡萄球菌是美国发病率和死亡率的主要原因。该应用程序的目标是确定金黄色葡萄球菌如何根据环境线索修改血红素贩运。这些实验将识别可能代表治疗靶点的新的血红素结合蛋白。

DESCRIPTION (provided by applicant): Staphylococcus aureus is a significant cause of morbidity and mortality in the United States. This pathogen is a major concern because of the increasing number of antibiotic resistant strains isolated from both hospital and community settings. Infection by S. aureus can cause a severe inflammatory response in all major organs. Like most pathogens, S. aureus requires iron for growth and the preferred iron source during infection is heme. Following heme acquisition, staphylococcal heme degrading enzymes catalyze the release of free iron. Heme can also be preferentially segregated to the membrane intact, presumably for use as a membrane cofactor. This suggests that S. aureus differentially utilizes heme depending on its metabolic needs. Paradoxically, many pathogens that acquire heme can also synthesize heme de novo. It is currently unknown how heme acquisition and heme synthesis are coordinated within the cell. Based on our preliminary data we hypothesize that heme is differentially sorted depending on whether it is exogenously acquired versus endogenously synthesized. This application proposes to test this hypothesis by identifying the molecular recipients of heme in the plasma membrane. These studies will significantly increase our understanding of staphylococcal heme trafficking and respiration, and may lead to the identification of novel therapeutic targets. The specific aims of this application are: Aim 1. Determine the intracellular fate of exogenously acquired heme within staphylococci. Aim 2. Define the physiological contributions of endogenous heme during staphylococcal infection. PUBLIC HEALTH RELEVANCE: Staphylococcus aureus is a major cause of morbidity and mortality in the United States. The goal of this application is to determine how S. aureus modifies heme trafficking in response to environmental cues. These experiments will identify novel heme-binding proteins that may represent therapeutic targets.