An Ftr1 vaccine to abrogate mucormycosis

描述（由申请人提供）：毛霉病是一种危及生命的感染，发生在因糖尿病酮症酸中毒、中性粒细胞减少症、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50%左右，而播散性疾病患者的死亡率接近100%。显然，迫切需要预防和治疗毛霉病的新策略。血清铁水平升高的患者对毛霉病特别敏感。这些患者包括糖尿病酮症酸中毒（DKA）和去铁胺治疗的患者。去铁胺作为一种外源性铁载体，为毛霉病提供以前无法获得的铁。我们已经证明，铁螯合剂与去铁胺以外的螯合剂可以保护小鼠免受米根霉感染，米根霉是最常见的从毛霉病患者身上分离出来的有机体。我们还证明了高亲和力的铁渗透酶（rFTR1）基因编码一种蛋白质（rFtr1p），该蛋白质是铁转运到真菌细胞所必需的，在体内表达，并且是米曲霉毒力所必需的。此外，我们发现，在感染前和感染后持续使用抗rftr1p抗体进行被动免疫，可显著提高感染米曲霉的小鼠的存活率。我们建议进一步明确抗rftr1p抗体对米曲霉的治疗效果和保护机制。此外，我们将确定抗rFtr1p抗体在感染其他毛霉菌、烟曲霉或白色念珠菌的小鼠中保护的广度和机制，因为rFtr1p与这些真菌的高亲和力铁渗透物具有相当大的同一性。抗rftr1p抗体辅助治疗潜力的原理证明将为RO1的应用奠定基础，进一步优化针对毛霉病的基于抗体的治疗策略，并开发保护性单克隆抗体。最终，定义rFtr1p作为抗体治疗靶点的作用，有可能为这些破坏性感染提供一种全新的治疗干预。

DESCRIPTION (provided by applicant): Mucormycosis is a life-threatening infection that occurs in patients immunocompromised by diabetic ketoacidosis, 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 >50%, and approaches 100% in patients with disseminated disease. Clearly new strategies to prevent and treat mucormycosis are urgently needed. Patients with elevated levels of available serum iron are uniquely susceptible to mucormycosis. These patients include diabetics in ketoacidosis (DKA) and deferoxamine- treated patients. Deferoxamine acts as a xeno-siderophore which supplies the agents of mucormycosis with previously unavailable iron. We have shown that iron chelation with chelators other than deferoxamine protects mice from infection with Rhizopus oryzae, the most commonly isolated organism from patients with mucormycosis. We also demonstrated that the high affinity iron permease (rFTR1) gene encodes a protein (rFtr1p) which is required for iron transport into the fungal cell, is expressed in vivo, and is required for virulence of R. oryzae. Further, we found that passive immunization with anti-rFtr1p antibodies initiated prior to and continued after infection markedly improves survival of mice with otherwise lethal R. oryzae infection. We propose to further define the therapeutic efficacy and mechanism of protection of anti-rFtr1p antibodies against R. oryzae. Additionally, we will determine the breadth and mechanism of protection of anti-rFtr1p antibodies in mice infected with other Mucorales, Aspergillus fumigatus or Candida albicans since rFtr1p has considerable identity to high affinity iron permeases from these fungi. Demonstration of proof of principle of the adjunctive therapeutic potential of anti-rFtr1p antibodies will provide a foundation for an RO1 application in which antibody-based therapeutic strategies will be further optimized against mucormycosis, and protective monoclonal antibodies will be developed. Ultimately, definition of the role of rFtr1p as a target for antibody treatment has the potential to enable a completely novel therapeutic intervention for these devastating infections. PUBLIC HEALTH RELEVANCE: Iron is essential for the growth of Rhizopus oryzae, a fungus that causes life-threatening infections in patients with diabetes, cancer, or other causes of weak immune systems. Current treatment options for mucormycosis are inadequate, and 50% or more of patients with mucormycosis die of the infection despite treatment. We propose to develop an antibody-based therapy that blocks the ability of the fungus to take up iron, thereby preventing its growth and improving the survival of infected patients.