title: Characterization of a 5-azacytidine-induced developmental Aspergillus fumigatus variant.
abstract: The hypomethylating agent 5-azacytidine (5AC) is widely used in patients at risk of invasive mycoses. We sought to determine whether 5AC affects the developmental competence and virulence of Aspergillus fumigatus. Incubation of A. fumigatus strain 293 with 5AC induced high-frequency conversion to a fluffy-variant (Af293 (FL) ). The conidiation defect was bypassed by exposing Af293 (FL) to light during the initial 18 hours of growth on solid media. Transcriptional profiling revealed differential expression of multiple genes involved in G-protein signaling, including a putative G-protein coupled photoreceptor (opsin), suggesting that impaired signaling through a light-responsive pathway upstream of brlA is responsible for this phenotype. Af293 (FL) was fully virulent in fruit fly and murine models of invasive aspergillosis. Moreover, Af293 (FL) overexpressed aspergillopepsin F, had increased elastase activity and was more angioinvasive than the parental wild-type strain. The 5AC-induced A. fumigatus fluffy variant illustrates the potential effects of chemotherapeutic agents on the developmental and pathobiologic characteristics of opportunistic fungi.
authors.affiliation: Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Ben-Ami
authors.forename: Varga
authors.initials: V
authors.lastname: Varga
authors.forename: Russell E
authors.initials: RE
authors.lastname: Lewis
authors.forename: Gregory S
authors.initials: GS
authors.lastname: May
authors.forename: William C
authors.initials: WC
authors.lastname: Nierman
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development* / Q000472:pathogenicity*; D001374:Azacitidine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000382:microbiology; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D014644:Genetic Variation; D005838:Genotype; D055744:Invasive Pulmonary Aspergillosis / Q000382:microbiology*; D008027:Light; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D014774:Virulence
chemical_list: D000964:Antimetabolites, Antineoplastic; D005656:Fungal Proteins; D001374:Azacitidine