Iron Uptake and Mucormycosis Pathogenesis

描述（由申请方提供）：毛霉菌病，最常见的是由根霉引起的毛霉菌病，是一种危及生命的感染，发生在因糖尿病酮症酸中毒（DKA）、中性粒细胞减少、皮质类固醇使用和/或血清铁升高而免疫功能低下的患者中。由于这些危险因素的流行率上升，毛霉菌病的发病率也有所上升。尽管进行了毁容手术和积极的抗真菌治疗，毛霉菌病的死亡率仍然> 40%，在播散性疾病患者中接近100%。显然，需要新的策略来预防和治疗毛霉菌病。 R.真菌感染包括其显著的血管生成性和血清铁水平升高的患者对真菌感染的易感性。血清铁水平升高的患者，如DKA患者或接受去铁胺治疗的患者，对毛霉菌病特别敏感，但对其他真菌感染不敏感。去铁胺作为一种异种铁载体，为真菌提供以前不可用的铁。我们已经证明，铁螯合剂不被真菌利用，以获得铁保护小鼠免受感染。- 是的我们还发现，高亲和力的铁通透酶（Ftr 1 p）是至关重要的真菌在感染过程中获得铁的能力。同样重要的是，我们最近鉴定了铁调节的GRP 78作为宿主细胞受体，R.在侵入内皮细胞的过程中结合，这是血管侵入所需的步骤。最后，我们发现抗Ftr 1 p或抗Grp 78抗体显著但不完全保护DKA小鼠免受R. - 是的这些发现强调了铁和血管内皮细胞的侵袭在生物体的毒力策略中的关键作用。我们建议建立在这些令人兴奋的数据，以进一步表征参与铁吸收和/或铁调节的真菌和宿主靶点。我们的目标是开发多种免疫策略，将被证明是协同预防和/或治疗致命的毛霉菌病。我们将通过鉴定参与介导R结合的真菌配体来实现这一目标。内皮细胞GRP 78。我们将继续确定宿主受体，而不是GRP 78，促进粘附和/或入侵和随后的损伤内皮细胞的R。- 是的此外，我们还将研究生理条件（包括铁）对体内GRP 78表达模式的影响。最后，我们将确定真菌受体Ftr 1 p的上游行为介导的铁从主机的吸收。 实现这些具体目标将进一步确定铁在毛霉菌病的建立和发展中的作用，并确定可能的新的治疗策略，可以同时应用于对疾病。

DESCRIPTION (provided by applicant): Mucormycosis, most commonly caused by Rhizopus oryzae, is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), neutropenia, corticosteroid use, and/or increased serum iron. Because of the rising prevalence of these risk factors, the incidence of mucormycosis has risen. Despite disfiguring surgery and aggressive antifungal therapy, the mortality of mucormycosis remains >40%, and approaches 100% in patients with disseminated disease. Clearly new strategies to prevent and treat mucormycosis are needed. Clinical hallmarks of R. oryzae infection include its remarkable angiotropism and the hypersusceptibility of patients with increased available serum iron to this infection. Patients with elevated levels of available serum iron such as those with DKA or who have received deferoxamine are uniquely susceptible to mucormycosis, but not other fungal infections. Deferoxamine acts as a xeno-siderophore which supplies previously unavailable iron to the fungus. We have shown that iron chelation with chelators that are not utilized by the fungus to obtain iron protects mice from infection with R. oryzae. We also found that the high affinity iron permease (Ftr1p) is critical to the ability of the fungus to obtain iron during infection. Equally important is our recent identification of the iron-regulated GRP78 as a host cell receptor to which R. oryzae binds during the process of invading endothelial cells, a step required for angioinvasion. Finally, we found that anti-Ftr1p or anti-Grp78 antibodies markedly, but not completely, protected DKA mice from infection with R. oryzae. These findings underscore the critical role of iron and invasion of vascular endothelial cells in the organism's virulence strategies. We propose to build on these exciting data to further characterize fungal and host targets that are involved in iron uptake and/or regulated by iron. Our goal is to develop multiple immunotherapeutic strategies that will prove to be synergistic in preventing and/or treating lethal mucormycosis. We will achieve this goal by identifying the fungal ligand involved in mediating binding of R. oryzae to endothelial cell GRP78. We will continue identifying host receptors, other than GRP78, that promote adherence to and/or invasion of and subsequent injury to endothelial cells by R. oryzae. Additionally, we will study the effect of physiological conditions, including iron, on the pattern of GRP78 expression in vivo. Finally, we will identify fungal receptors which act upstream of Ftr1p in mediating iron uptake from the host. Achieving these specific aims will further define the role of iron in the establishment and progression of mucormycosis and define possible novel therapeutic strategies that can be applied concurrently against the disease.