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(申请人提供)：毛霉菌病是一种危及生命的感染，发生在由于糖尿病酮症酸中毒、中性粒细胞减少、皮质类固醇使用和/或血清铁升高而导致的免疫功能低下的患者中。由于这些危险因素的患病率上升，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%，在播散性疾病患者中接近100%。显然，迫切需要新的策略来预防和治疗毛霉病。血清有效铁水平升高的患者特别容易患毛霉病。这些患者包括酮症酸中毒(DKA)的糖尿病患者和接受去铁胺治疗的患者。去铁胺起到了异种铁载体的作用，为毛霉菌病提供了以前无法获得的铁。我们已经证明，除去铁胺外，铁络合剂可以保护小鼠免受米根霉的感染，米根霉是毛霉病患者最常见的分离生物。我们还证明了高亲和力铁渗透酶(RFTR1)基因编码了一种蛋白质(RFtr1p)，它是铁进入真菌细胞所必需的，在体内表达，是水稻纹枯病菌致病所必需的。此外，我们发现，在感染前开始并在感染后继续使用抗rFtr1p抗体的被动免疫显著提高了感染其他致命性稻瘟病菌的小鼠的存活率。我们建议进一步明确抗rFtr1p抗体对稻瘟病菌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的广度和保护机制，因为rFtr1p与这些真菌的高亲和力铁渗透有相当大的相似性。抗rFtr1p抗体辅助治疗潜力的原理证明的证明将为RO1的应用奠定基础，在该应用中，基于抗体的治疗策略将进一步优化对毛霉病的治疗策略，并将开发保护性的单抗。最终，rFtr1p作为抗体治疗靶点的定义有可能为这些毁灭性感染提供一种全新的治疗干预措施。 与公共卫生相关：铁对米根霉的生长至关重要，米根霉是一种真菌，会在糖尿病、癌症或其他免疫系统薄弱的患者中引起危及生命的感染。目前毛霉病的治疗选择不足，50%或更多的毛霉病患者尽管接受了治疗，仍死于感染。我们建议开发一种基于抗体的治疗方法，阻止真菌吸收铁的能力，从而防止其生长并提高感染患者的存活率。