Iron Uptake and Mucormycosis Pathogenesis

毛霉菌病是一种威胁生命的感染，发生在糖尿病患者的免疫功能低下 酮症酸中毒、中性粒细胞减少、类固醇使用和/或血清铁升高。因为风险的流行程度不断上升 因素，毛霉病的发病率急剧增加(根据一位专家的说法，15年来增加了1300% 来源)。尽管进行了毁容手术和积极的抗真菌治疗，毛霉病的死亡率 在播散性疾病患者中保持50%，接近100%。显然是新的战略来 预防和治疗毛霉病迫在眉睫。 感染米根霉是毛霉病的最常见原因，其临床特征包括 患者的独特易感性与可利用的血清铁、有机体侵袭的倾向 血管和吞噬功能缺陷，我们推测这至少部分是铁的结果 毒性。这些临床特征强调了铁代谢的关键作用，以及与 血管内皮细胞，在生物体的毒力策略中。我们发现了稻瘟病菌 在体外损害内皮细胞，这一过程依赖于铁。此外，我们还克隆了R。 水稻高亲和力铁渗透酶(RFTR1)，从缺铁环境(如IS)中清除铁 在宿主体内发现的。最后，我们建立了临床相关的糖尿病酮症酸中毒感染模型。 老鼠。我们推测，铁摄取，特别是rFTR1，是水稻纹枯病菌引起感染所必需的。 为了验证这一假说，我们建议：1)刻画铁调控水稻纹枯病菌的机制(S)。 诱导内皮细胞损伤；2)构建rftrl缺失突变体及其相应的rFTR1 利用定点突变技术对补充菌株jn R.oryzae进行了致病性比较。 在我们的体外和体内模型中，rftrl与野生型和rftr1互补株产生的rftrl。 4)阐明铁在调节天然寄主对水稻纹枯病菌的反应中的作用。 实现这些具体目标将确定影响建制的中心因素的作用 和毛霉病的进展，因为它与铁摄取有关。归根结底，对 毛霉病的发病机制将使这种疾病的新疗法的发展成为可能。完成 拟议的研究将使人们能够研究阻止稻曲霉吸收铁的处理方法。

Mucormycosis is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis, neutropenia, steroid use, and/or increased serum iron. Because of the rising prevalence of risk factors, the incidence of mucormycosis has dramatically increased (1300% over 15 years according to one source). Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >50%, and approaches 100% in patients with disseminated disease. Clearly new strategies to prevent and treat mucormycosis are urgently needed. Clinical hallmarks of infection by Rhizopus oryzae, the most common cause of mucormycosis, include the unique susceptibility of patients with increased available serum iron, the propensity of the organism to invade blood vessels, and defective phagocytic function, which we hypothesize to be, at least in part, a result of iron toxicity. These clinical hallmarks underscore the critical role of iron metabolism, as well as interactions with endothelial cells lining blood vessels, in the organism's virulence strategy. We have found that R. oryzae damages endothelial cells in vitro and this process is dependent on iron. Additionally, we have cloned the R. oryzae high affinity iron permease (rFTR1) which scavenges iron from iron-depleted environments such as is found in the host. Finally we have developed clinically relevant models of infection in diabetic ketoacidotic mice. We hypothesize that iron uptake, and specifically rFTR1, is essential for R. oryzae to cause infection. To test this hypothesis, we propose to: 1) characterize the mechanism(s) by which iron regulates R. oryzae- induced endothelial cell injury; 2) construct an isogenic rftrl null mutant and its corresponding rFTR1 complemented strain jn R. oryzae by site directed mutagenesis; 3) compare the pathogenicity of the generated rftrl to that of the wild-type and rFTR1 complemented strains in our in vitro and in vivo models of infection; and 4) elucidate the role of iron in regulating the innate host response to R. oryzae. Accomplishing these specific aims will define the role of the central elements affecting the establishment and progression of mucormycosis as it relates to iron uptake. Ultimately, a superior understanding of the pathogenesis of mucormycosis will enable development of novel therapies for this disease. Completion of the proposed studies will enable investigation of treatments that block R. oryzae uptake of iron.