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.
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.
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