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。由于从医院和社区环境中分离出越来越多的抗生素耐药菌株，这种病原体成为一个主要问题。金黄色葡萄球菌感染可引起所有主要器官的严重炎症反应。像大多数病原体一样，金黄色葡萄球菌需要铁来生长，而在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游离铁的释放。血红素也可以被优先分离到完整的膜上，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。矛盾的是，许多获得血红素的病原体也可以重新合成血红素。目前尚不清楚血红素获取和血红素合成是如何在细胞内协调的。根据我们的初步数据，我们假设血红素的分类取决于它是外源性获得还是内源性合成。本应用建议通过鉴定质膜中血红素的分子受体来验证这一假设。这些研究将显著增加我们对葡萄球菌血红素运输和呼吸的理解，并可能导致新的治疗靶点的确定。此应用程序的具体目标是：目标1。确定葡萄球菌内外源性获得血红素的细胞内命运。目标2。确定葡萄球菌感染期间内源性血红素的生理贡献。

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.