An Ftr1 vaccine to abrogate mucormycosis

消除毛霉菌病的 Ftr1 疫苗

• 批准号: 8020985
• 负责人: ASHRAF S. IBRAHIM
• 金额: $ 20.52万
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020985
• 关键词: Absidia; Acidosis; Adrenal Cortex Hormones; Affinity; Aging; Amphotericin B Liposomal; Antibodies; Antifungal Therapy; Aspergillosis; Aspergillus; Aspergillus fumigatus; Blinded; Breathing; Candida albicans; Cells; Central Nervous System Diseases; Cessation of life; Chelating Agents; Cunninghamella; Debridement; Deferoxamine; Development; Diabetes Mellitus; Diabetic Ketoacidosis; Disease; Disseminated candidiasis; Dissociation; Foundations; Genes; Growth; Human; Immune; Immune Sera; Immune system; Immunocompromised Host; Immunotherapeutic agent; In Vitro; Incidence; Infection; Inflammatory Response; Intravenous; Iron; Iron Chelation; Lead; Life; Lung; Malignant Neoplasms; Mediating; Modeling; Monoclonal Antibodies; Mucor; Mucorales; Mucormycosis; Mus; Neutropenia; Operative Surgical Procedures; Organ; Organ Transplantation; Organism; Oryza; Passive Immunization; Pathogenesis; Patients; Phagocytes; Pharmaceutical Preparations; Population; Prevalence; Proteins; Protons; Recombinants; Reporting; Research Personnel; Rhizopus; Risk; Risk Factors; Role; Serum; Siderophores; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; United States; Vaccinated; Vaccines; Virulence; Xeno; Zygomycosis; base; diabetic; fungus; improved; in vivo; iron metabolism; mortality; mouse model; novel therapeutic intervention; novel therapeutics; passive antibodies; permease; prevent; public health relevance; uptake

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.

描述（由申请人提供）：粘膜细胞增多是一种威胁生命的感染，发生在糖尿病性酮症酸中毒，中性粒细胞减少症，皮质类固醇使用和/或血清铁升高的患者中。由于这些危险因素的患病率上升，粘膜菌病的发生率增加了。尽管毁容手术和侵略性抗真菌疗法，但粘膜菌病的死亡率仍然> 50％，并且在散布疾病的患者中接近100％。显然，迫切需要采取预防和治疗粘膜菌病的新策略。 可用的血清铁水平升高的患者易受粘霉菌病的特殊敏感。这些患者包括酮症酸中毒（DKA）和脱氧胺治疗的患者的糖尿病患者。脱铁胺充当异种基载体，可为粘膜菌病提供以前无法获得的铁。我们已经表明，除脱氧胺以外的其他螯合剂的铁螯合可保护小鼠免受粘膜菌病患者最常见的生物体的感染。我们还证明，高亲和力的铁粘酶（RFTR1）基因编码铁转入真菌细胞所需的蛋白质（RFTR1P），在体内表达，这是R. oryzae的毒力所必需的。此外，我们发现，在感染前并在感染明显提高了抗死抗体的抗RFTR1P抗体的被动免疫可显着提高小鼠的生存率，否则致命的R. oryzae感染了。我们建议进一步定义抗RFTR1P抗体抗体抗体的治疗功效和机制。此外，由于RFTR1P对这些真菌的高亲和力铁蛋白酶具有相当大的认同，因此我们将确定在感染其他粘膜，烟草曲霉或念珠菌的小鼠中保护抗RFTR1P抗体的广度和机制。 抗RFTR1P抗体的辅助治疗潜力原理证明的证明将为RO1应用提供基础，在该应用中，基于抗体的治疗策略将进一步针对粘膜菌病进行优化，并开发了保护性的单克隆抗体。最终，对RFTR1P作为抗体治疗靶标的作用的定义有可能使这些毁灭性感染具有完全新颖的治疗干预措施。 公共卫生相关性：铁对于Rhizopus Oryzae的生长至关重要，Rhizopus Oryzae是一种真菌，会导致糖尿病，癌症或其他免疫系统弱原因威胁生命的感染。当前的粘膜细胞病治疗选择不足，尽管治疗，但50％或更多的粘膜细胞增多症患者死于感染。我们建议开发一种基于抗体的疗法，以阻止真菌吸收铁的能力，从而防止其生长并改善感染患者的生存。