Transferrin Enhances Antifungal Therapy and Improves Survival in Experimental Mucormycosis

Mucormycosis is a highly lethal invasive fungal infection caused by fungi of the order Mucorales, with mortality rates exceeding 50% despite current antifungal therapies with polyenes or azoles. Because iron acquisition is essential for Mucorales growth and virulence, we investigated whether transferrin, the primary physiological iron-sequestering protein in plasma, could serve as a host-directed therapeutic strategy against mucormycosis. Transferrin inhibited the growth of clinically relevant Mucorales species, including Rhizopus delemar (R. delemar), Rhizomucor, and Lichtheimia corymbifera (L. corymbifera) in a concentration-dependent manner. Checkerboard assays demonstrated synergistic interactions between transferrin and liposomal amphotericin B (LAMB), with fractional inhibitory concentration index values below 0.5 for all tested species. In endothelial cell infection model, transferrin significantly reduced expression of the fungal invasion ligand spore coat protein homolog 3 (CotH3) and the host receptor glucose-regulated protein 78 (GRP78), key mediators of angioinvasion during mucormycosis. In a neutropenic murine model of pulmonary mucormycosis, transferrin enhanced the therapeutic efficacy of both LAMB and isavuconazole (ISAV), resulting in improved survival compared with antifungal monotherapy. Collectively, these findings provide preclinical evidence that transferrin modulates pathogenic determinants associated with mucormycosis and enhances the efficacy of current antifungal therapies, supporting further investigation of transferrin as a potential host-directed adjunctive treatment.