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Drosophila melanogaster as a model host to dissect the immunopathogenesis of zygomycosis

Chamilos, Georgios, Lewis, Russell E., Hu, Jianhua, Xiao, Lianchun, Zal, Tomasz, Gilliet, Michel, Halder, Georg, Kontoyiannis, Dimitrios P.
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.27 pp. 9367-9372
Aspergillus fumigatus, Drosophila melanogaster, adrenal cortex hormones, antimicrobial peptides, chelating agents, defense mechanisms, deferoxamine, fungal spores, fungi, gene expression regulation, gene overexpression, genes, host-pathogen relationships, humans, hyphae, immune response, models, mutants, mycoses, pathogens, phagocytes, phagocytosis, steroid metabolism, stress response, tissue repair, transgenic insects, virulence
Zygomycosis is an emerging frequently fatal opportunistic mycosis whose immunopathogenesis is poorly understood. We developed a zygomycosis model by injecting Drosophila melanogaster flies with a standardized amount of fungal spores from clinical Zygomycetes isolates to study virulence and host defense mechanisms. We found that, as opposed to most other fungi, which are nonpathogenic in D. melanogaster (e.g., Aspergillus fumigatus), Zygomycetes rapidly infect and kill wild-type flies. Toll-deficient flies exhibited increased susceptibility to Zygomycetes, whereas constitutive overexpression of the antifungal peptide Drosomycin in transgenic flies partially restored resistance to zygomycosis. D. melanogaster Schneider 2 phagocytic cells displayed decreased phagocytosis and caused less hyphal damage to Zygomycetes compared with that to A. fumigatus. Furthermore, phagocytosis-defective eater mutant flies displayed increased susceptibility to Zygomycetes infection. Classic enhancers of Zygomycetes virulence in humans, such as corticosteroids, increased iron supply, and iron availability through treatment with deferoxamine dramatically increased Zygomycetes pathogenicity in our model. In contrast, iron starvation induced by treatment with the iron chelator deferasirox significantly protected flies infected with Zygomycetes. Whole-genome expression profiling in wild-type flies after infection with Zygomycetes vs. A. fumigatus identified genes selectively down-regulated by Zygomycetes, which act in pathogen recognition, immune defense, stress response, detoxification, steroid metabolism, or tissue repair or have unknown functions. Our results provide insights into the factors that mediate host-pathogen interactions in zygomycosis and establish D. melanogaster as a promising model to study this important mycosis.