Drosophila melanogaster as a model host to dissect the immunopathogenesis of zygomycosis.
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.
Chamilos
Georgios
G
Department of Infectious Diseases, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Lewis
Russell E
RE
Hu
Jianhua
J
Xiao
Lianchun
L
Zal
Tomasz
T
Gilliet
Michel
M
Halder
Georg
G
Kontoyiannis
Dimitrios P
DP
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000472:pathogenicity; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000382:microbiology*; D005658:Fungi / Q000187:drug effects / Q000302:isolation & purification / Q000472:pathogenicity; D005786:Gene Expression Regulation / Q000187:drug effects; D017344:Genes, Insect; D006801:Humans; D025301:Hyphae / Q000187:drug effects / Q000502:physiology; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014774:Virulence / Q000187:drug effects; D020096:Zygomycosis / Q000276:immunology* / Q000473:pathology*
D023181:Antimicrobial Cationic Peptides; D029721:Drosophila Proteins; D012333:RNA, Messenger; C091227:DRS protein, Drosophila; C096696:Mtk protein, Drosophila; D003907:Dexamethasone