ABSTRACT
Invasive fungal diseases cause millions of deaths each year. There are currently approximately 300,000 acute cases of aspergillosis, most of which result from a pulmonary infection of immunocompromised patients by the common soil organism and opportunistic pathogen Aspergillus fumigatus. Patients are treated with antifungal drugs, such as amphotericin B (AmB). However, AmB has serious limitations due to human organ toxicity. AmB is slightly less toxic if loaded in liposomes, such as AmBisome or AmB-loaded liposomes (AmB-LLs). Even with antifungal therapy, recurrent infections are common, and 1-year fatality rates may exceed 50%. We have previously shown that coating AmB-LLs with the extracellular oligomannan-binding domain of the C-type lectin receptor Dectin-2 (DEC2-AmB-LLs) effectively targets DEC2-AmB-LLs to cell walls, exopolysaccharide matrices, and biofilms of fungal pathogens in vitro. In vitro, DEC2-AmB-LLs reduce the effective dose of AmB for 95% inhibition and killing of A. fumigatus 10-fold compared to that of untargeted AmB-LLs. Herein we tested the antifungal activity of DEC2-AmB-LLs relative to that of untargeted AmB-LLs in immunosuppressed mice with pulmonary aspergillosis. Remarkably, DEC2-AmB-LLs bound 30-fold more efficiently to A. fumigatus at sites of infection in the lungs. Furthermore, Dectin-2-targeted liposomes delivering AmB at a dose of 0.2 mg/kg of body weight significantly reduced the fungal burden in lungs compared to results with untargeted AmB-LLs at 0.2 mg/kg and micellar voriconazole at 20 mg/kg and prolonged mouse survival. By dramatically increasing the efficacy of antifungal drugs at low doses, targeted liposomes have the potential to create a new clinical paradigm to treat diverse fungal diseases.
IMPORTANCE Invasive aspergillosis (IA) generally results from a pulmonary infection of immunocompromised patients by the common soil organism and opportunistic pathogen Aspergillus fumigatus. The susceptible population has expanded rapidly due to the increased number of cancer patients with immunocompromising chemotherapy and transplant patients taking immunosuppressants. Patients are treated with antifungals, such as liposomal amphotericin B, with per-patient costs exceeding $50,000 in the United States. However, AmB has serious side effects due to host toxicity, which limits its usage and contributes to the lack of fungal clearance in patients at safe doses. Fifty percent of IA patients die within a year. Herein, we employed liposomal amphotericin B coated with the innate immune receptor Dectin-2 to direct antifungals specifically to the fungal pathogen. Using two mouse models of pulmonary aspergillosis, we demonstrate that Dectin-2-targeted delivery of amphotericin B to A. fumigatus resulted in remarkably higher efficacy than that of the untargeted antifungal formulations.
Unusual presentation of pulmonary blastomycosis complicated by amphotericin-induced refractory electrolyte abnormalities
