Iron Uptake and Mucormycosis Pathogenesis

铁摄取和毛霉菌病发病机制

• 批准号: 7556321
• 负责人: ASHRAF S. IBRAHIM
• 金额: $ 26.94万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7556321
• 关键词: Affect; Affinity; Aging; Angioinvasion; Animal Model; Animals; Antifungal Therapy; Biological Assay; Blood Vessels; Cell Line; Cells; Chelating Agents; Clinical; Complement; Debridement; Development; Diabetes Mellitus; Diabetic Ketoacidosis; Diabetic mouse; Disease; Down-Regulation; Elements; Endothelial Cells; Environment; Functional disorder; Generations; Genes; Hematogenous; Histology; Host Defense; Immune response; Immunocompromised Host; In Vitro; Incidence; Infection; Invaded; Investigation; Iron; Iron Overload; Life; Malignant Neoplasms; Mediating; Methods; Modeling; Mucormycosis; Mus; Neutropenia; Operative Surgical Procedures; Organ Transplantation; Organism; Oryza; Pathogenesis; Pathogenicity; Patients; Penetration; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Population; Predisposition; Prevalence; Process; Production; Reporting; Research Personnel; Rhizopus; Risk; Risk Factors; Role; Serum; Site-Directed Mutagenesis; Source; Steroids; Techniques; Testing; Time; Toxic effect; United States; Virulence; cell injury; clinically relevant; cytokine; fungus; genetic manipulation; in vivo; in vivo Model; iron metabolism; mortality; mutant; neutrophil; non-diabetic; novel; permease; prevent; process optimization; programs; reactive oxygen intermediate; receptor; response; tissue tropism; uptake

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.

粘膜细胞增多是一种威胁生命的感染，发生在糖尿病的免疫功能低下的患者中 酮症酸中毒，中性粒细胞减少，类固醇使用和/或血清铁增加。由于风险的普遍性上升 因素，粘膜细胞增多的发生率已大大增加（在15年内1300％ 来源）。尽管手术和侵略性抗真菌疗法毁容，但粘膜细胞增多的死亡率 保持> 50％，在传播疾病的患者中接近100％。显然是新的策略 迫切需要预防和治疗粘膜菌病。 莫氏菌病的最常见原因包括麦麦乳菌的临床标志，包括 可用的血清铁增加的患者的独特敏感性，有机体侵入的倾向 血管和缺陷的吞噬功能，我们假设这至少部分是铁的结果 毒性。这些临床标志强调了铁代谢的关键作用，以及与 在生物体的毒力策略中，内皮细胞衬有血管。我们发现R. Oryzae 在体外损害内皮细胞，此过程取决于铁。此外，我们已经克隆了R。 Oryzae高亲和力铁粘酶（RFTR1），它从耗资耗尽的环境中清除铁 在主机中发现。最后，我们开发了糖尿病性酮酸酸性感染与临床相关的感染模型 老鼠。我们假设铁的摄取，尤其是RFTR1，对于R. oryzae引起感染至关重要。 为了检验这一假设，我们建议：1）表征铁调节。 诱发内皮细胞损伤； 2）构建一个等基因RFTRL空突变体及其相应的RFTR1 通过位点定向诱变的补充菌株Jn R. Oryzae； 3）比较 在我们的体外和体内模型中，生成野生型和RFTR1菌株的RFTRL 感染; 4）阐明铁在调节天生宿主对R. oryzae的反应中的作用。 实现这些特定目标将定义影响机构的中心因素的作用 与铁吸收有关的粘膜菌病的进展。最终，对 粘膜细胞增多的发病机理将使该疾病的新疗法发展。完成 拟议的研究将对阻断铁菌摄取铁的治疗方法进行研究。