title: A subdose of fluconazole alters the virulence of Cryptococcus gattii during murine cryptococcosis and modulates type I interferon expression.
abstract: Cryptococcosis is an invasive infection caused by yeast-like fungus of the genera Cryptococcus spp. The antifungal therapy for this disease provides some toxicity and the incidence of infections caused by resistant strains increased. Thus, we aimed to assess the consequences of fluconazole subdoses during the treatment of cryptococcosis in the murine inflammatory response and in the virulence factors of Cryptococcus gattii. Mice infected with Cryptococcus gattii were treated with subdoses of fluconazole. We determined the behavior of mice and type 1 interferon expression during the treatment; we also studied the virulence factors and susceptibility to fluconazole for the colonies recovered from the animals. A subdose of fluconazole prolonged the survival of mice, but the morbidity of cryptococcosis was higher in treated animals. These data were linked to the increase in: (i) fluconazole minimum inhibitory concentration, (ii) capsule size and (iii) melanization of C. gattii, which probably led to the increased expression of type I interferons in the brains of mice but not in the lungs. In conclusion, a subdose of fluconazole altered fungal virulence factors and susceptibility to this azole, leading to an altered inflammatory host response and increased morbidity.
authors.affiliation: Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Alide Caroline Lima
authors.initials: AC
authors.lastname: Fontes
authors.affiliation: Laboratório de Vírus, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.|Universidade Federal do Vale do Jequitinhonha e Mucuri, Diamantina, Minas Gerais, Brazil.
authors.forename: Danilo
authors.initials: D
authors.lastname: Bretas Oliveira
authors.affiliation: Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.|Laboratório de Micologia, Universidade Ceuma (UNICEUMA), São Luís, Maranhão, Brazil.
authors.forename: Juliana Ribeiro Alves
authors.initials: JR
authors.lastname: Santos
authors.affiliation: Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Hellem Cristina Silva
authors.initials: HC
authors.lastname: Carneiro
authors.affiliation: Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Noelly de Queiroz
authors.initials: NQ
authors.lastname: Ribeiro
authors.affiliation: Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Lorena Vívien Neves de
authors.initials: LV
authors.lastname: Oliveira
authors.affiliation: Laboratório de Biologia de fungos de importância médica e biotecnológica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil.
authors.forename: Vanessa Abreu
authors.initials: VA
authors.lastname: Barcellos
authors.affiliation: Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Tatiane Alves
authors.initials: TA
authors.lastname: Paixão
authors.affiliation: Laboratório de Vírus, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Jonatas Santos
authors.initials: JS
authors.lastname: Abrahão
authors.affiliation: Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
authors.forename: Maria Aparecida
authors.initials: MA
authors.lastname: Resende-Stoianoff
authors.affiliation: Laboratório de Biologia de fungos de importância médica e biotecnológica, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Rio Grande do Sul, Brazil.
authors.forename: Marilene Henning
authors.initials: MH
authors.lastname: Vainstein
authors.affiliation: Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil das@ufmg.br.
authors.forename: Daniel Assis
authors.initials: DA
authors.lastname: Santos
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003453:Cryptococcosis / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology*; D056285:Cryptococcus gattii / Q000187:drug effects* / Q000472:pathogenicity*; D004195:Disease Models, Animal; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage / Q000494:pharmacology*; D007370:Interferon Type I / Q000096:biosynthesis*; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D016019:Survival Analysis; D014774:Virulence / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D007370:Interferon Type I; D015725:Fluconazole
keywords: inflammatory response; resistance; systemic mycosis; treatment; virulence factors