Iron Uptake and Mucormycosis Pathogenesis

毛霉菌病是一种危及生命的感染，发生在糖尿病患者的免疫功能低下， 酮症酸中毒、中性粒细胞减少症、类固醇使用和/或血清铁增加。由于风险的上升 由于这些因素，毛霉菌病的发病率急剧增加（根据一项研究，15年内增加了1300 来源）。尽管进行了毁容手术和积极的抗真菌治疗， 仍> 50%，在播散性疾病患者中接近100%。显然，新的战略 毛霉菌病的防治是迫切需要的。 毛霉菌病最常见的致病菌--毛霉根霉感染的临床特征包括： 血清铁增加的患者的独特易感性，生物体侵入的倾向， 血管和吞噬功能缺陷，我们假设这是，至少部分，铁的结果 毒性这些临床特征强调了铁代谢的关键作用，以及与铁代谢的相互作用。 内皮细胞内衬血管，在有机体的毒力策略。我们发现R.米 在体外损伤内皮细胞，并且该过程依赖于铁。此外，我们还克隆了R。 高亲和力铁通透酶（rFTR 1），其从铁耗尽的环境中清除铁， 在主机中找到。最后，我们开发了临床相关的糖尿病酮症酸中毒感染模型， 小鼠我们假设铁的摄取，特别是rFTR 1，是R。引起感染。 为了验证这一假设，我们建议：1）表征铁调节R的机制。- 诱导内皮细胞损伤; 2）构建同基因rFTR无效突变体及其相应的rFTR 1 互补菌株jn R.通过定点突变对稻进行诱变; 3）比较稻的致病性 在我们的体外和体内模型中， 阐明铁在调节宿主对R. - 是的 实现这些具体目标将确定影响建立的中心要素的作用， 和毛霉菌病的进展，因为它与铁的吸收有关。最后，一个上级的理解 毛霉菌病的发病机理将使得能够开发用于该疾病的新疗法。完成 这项研究将使阻断R的治疗方法成为可能。铁的吸收。

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.