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）：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、中性粒细胞减少症、皮质类固醇使用和/或血清铁增加而免疫功能低下的患者中。由于这些危险因素的患病率不断上升，毛霉菌病的发病率也随之上升。尽管进行毁容手术和积极的抗真菌治疗，毛霉菌病的死亡率仍然>50%，并且在患有播散性疾病的患者中接近100%。显然，迫切需要预防和治疗毛霉菌病的新策略。 可用血清铁水平升高的患者特别容易患毛霉菌病。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。去铁胺作为异种铁载体，为毛霉菌病病原体提供以前无法获得的铁。我们已经证明，铁与去铁胺以外的螯合剂的螯合可以保护小鼠免受米根霉（Rhizopus oryzae）的感染，米根霉是从毛霉菌病患者中最常见的分离微生物。我们还证明，高亲和力铁通透酶（rFTR1）基因编码一种蛋白质（rFtr1p），该蛋白质是将铁转运到真菌细胞中所需的，在体内表达，并且是米根霉毒力所必需的。此外，我们发现在感染之前开始并在感染后继续使用抗 rFtr1p 抗体被动免疫可显着提高感染米根霉的小鼠的存活率。我们建议进一步明确抗 rFtr1p 抗体对米根霉的治疗功效和保护机制。此外，我们将确定抗 rFtr1p 抗体对感染其他毛霉目、烟曲霉或白色念珠菌的小鼠的保护广度和机制，因为 rFtr1p 与来自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应用奠定基础，其中将进一步优化基于抗体的毛霉菌病治疗策略，并开发保护性单克隆抗体。最终，rFtr1p 作为抗体治疗靶点的作用的定义有可能为这些破坏性感染提供全新的治疗干预。 公共健康相关性：铁对于米根霉的生长至关重要，米根霉是一种真菌，会导致患有糖尿病、癌症或其他免疫系统薄弱原因的患者出现危及生命的感染。目前针对毛霉菌病的治疗方案不足，尽管接受了治疗，但仍有 50% 或更多的毛霉菌病患者死于感染。我们建议开发一种基于抗体的疗法，阻止真菌吸收铁的能力，从而阻止其生长并提高感染患者的生存率。

项目成果

Pathogenesis of mucormycosis.

毛霉菌病的发病机制。

• 发表时间: 2012-02
• 作者: Ibrahim, Ashraf S;Spellberg, Brad;Walsh, Thomas J;Kontoyiannis, Dimitrios P
• 通讯作者: Kontoyiannis, Dimitrios P

The high affinity iron permease is a key virulence factor required for Rhizopus oryzae pathogenesis.

高亲和力铁渗透酶是米根霉发病机制所需的关键毒力因子。

• 发表时间: 2010-08
• 影响因子: 3.6
• 作者: Ibrahim, Ashraf S;Gebremariam, Teclegiorgis;Lin, Lin;Luo, Guanpingsheng;Husseiny, Mohamed I;Skory, Christopher D;Fu, Yue;French, Samuel W;Edwards Jr, John E;Spellberg, Brad
• 通讯作者: Spellberg, Brad

Host cell invasion in mucormycosis: role of iron.

毛霉菌病中的宿主细胞侵袭：铁的作用。

• 发表时间: 2011-08
• 影响因子: 5.4
• 作者: Ibrahim; Ashraf S
• 通讯作者: Ashraf S

Diabetic murine models for Acinetobacter baumannii infection.

鲍曼不动杆菌感染的糖尿病小鼠模型。

• DOI: 10.1093/jac/dks050
• 发表时间: 2012-03-02
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: G. Luo;B. Spellberg;Teclegiorgis Gebremariam;M. Bolaris;Hongkyu Lee;Yue Fu;S. French;A. Ibrahim
• 通讯作者: A. Ibrahim