Human Dectin-1- and Dectin-2-targeted DectiSomes are effective against diverse pathogenic fungi

Annually, aspergillosis, candidiasis, cryptococcosis, and mucormycosis result in approximately 1,500,000, 650,000, 120,000, and 59,000 deaths, respectively. Mortality rates among patients receiving antifungal drug treatment range from 30% to 90%. Therefore, there is an urgent need to improve the efficacy of antifungal drug therapies against infections by these high-priority fungal diseases. Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Rhizopus delemar are the most common causative pathogens. We have previously developed DectiSomes, which are liposomes loaded with antifungal drugs and coated with the carbohydrate recognition domains of mouse Dectin-1 and/or Dectin-2. We demonstrated that the murine DectiSomes efficiently bound and killed these pathogens growing in vitro and/or in mouse disease models. With the plan to move DectiSomes into the clinic with the human Dectin orthologs, we were concerned that the significant sequence divergence between mouse and human Dectin-1 and Dectin-2 carbohydrate recognition domains could have altered pathogen specificity. Herein, we compared the functionality of the human and mouse Dectin-1 and Dectin-2 orthologs in targeting DectiSomes to these pathogens. Binding and growth inhibition data on A. fumigatus and C. neoformans supported their functional similarity, while results with C. albicans and R. delemar indicated some functional divergence. Despite these differences, our results demonstrate that both human and mouse DectiSomes are effective at binding and killing all four diverse fungal pathogens.