Iron Uptake and Mucormycosis Pathogenesis

描述（由申请人提供）：毛霉病，最常由米根霉引起，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不断上升，毛霉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，毛霉病的死亡率仍然保持在40%左右，而播散性疾病患者的死亡率接近100%。显然，预防和治疗毛霉病需要新的策略。米曲霉感染的临床特征包括其显著的血管趋近性和血清铁含量增加的患者对这种感染的超敏感。血清铁水平升高的患者，如DKA患者或接受过去铁胺治疗的患者，对毛霉病易感，但对其他真菌感染不敏感。去铁胺作为一种外源性铁载体，为真菌提供以前无法获得的铁。我们已经证明，铁螯合剂的铁螯合作用不被真菌利用来获得铁，保护小鼠免受米曲霉感染。我们还发现，高亲和力的铁渗透酶（Ftr1p）对真菌在感染期间获得铁的能力至关重要。同样重要的是，我们最近发现了铁调控的GRP78作为宿主细胞受体，R. oryzae在入侵内皮细胞的过程中与之结合，这是血管入侵所需的一个步骤。最后，我们发现抗ftr1p或抗grp78抗体显著但不完全地保护DKA小鼠免受米曲弧菌感染。这些发现强调了铁和血管内皮细胞入侵在机体毒力策略中的关键作用。我们建议以这些令人兴奋的数据为基础，进一步表征真菌和宿主参与铁摄取和/或受铁调节的靶标。我们的目标是开发多种免疫治疗策略，这些策略将被证明在预防和/或治疗致死性毛霉病方面具有协同作用。我们将通过鉴定参与介导R. oryzae与内皮细胞GRP78结合的真菌配体来实现这一目标。我们将继续鉴定GRP78以外的宿主受体，以促进米曲霉对内皮细胞的粘附和/或侵袭和随后的损伤。此外，我们将研究包括铁在内的生理条件对体内GRP78表达模式的影响。最后，我们将鉴定在Ftr1p上游介导宿主铁摄取的真菌受体。实现这些具体目标将进一步确定铁在毛霉病的建立和进展中的作用，并确定可能的新治疗策略，可以同时应用于该疾病。

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.