title: The ABC transporter-encoding gene AFR1 affects the resistance of Cryptococcus neoformans to microglia-mediated antifungal activity by delaying phagosomal maturation.
abstract: The pathogenic yeast Cryptococcus neoformans has evolved several strategies to survive within phagocytes. Recently, it has been demonstrated that upregulation of the ATP binding cassette transporter-encoding gene antifungal resistance 1 (AFR1) is important not only for determining the resistance of C. neoformans to fluconazole but also in influencing fungal virulence. In the present study, we showed that the fluconazole-resistant AFR1-overexpressing mutant strain was not sensitive to microglia-mediated anticryptococcal activity, as compared with the fluconazole-susceptible isogenic strains, the wild type and the afr1Delta mutant. Interestingly, although the three strains were phagocytosed to a similar extent, reduced acidification and delayed maturation were observed in phagosomes containing the AFR1-overexpressing strain with respect to the others. These findings provide the first evidence that upregulation of the AFR1 gene affects C. neoformans-microglia interplay, adding insights to the complexity of cryptococcal virulence and to its unexpected link with azole resistance.
authors.affiliation: Dipartimento di Scienze di Sanità Pubblica, Università di Modena e Reggio Emilia, Modena, Italy.
authors.forename: Carlotta Francesca
authors.initials: CF
authors.lastname: Orsi
authors.forename: Bruna
authors.initials: B
authors.lastname: Colombari
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
authors.forename: Samuele
authors.initials: S
authors.lastname: Peppoloni
authors.forename: Rachele
authors.initials: R
authors.lastname: Neglia
authors.forename: Brunella
authors.initials: B
authors.lastname: Posteraro
authors.forename: Giulia
authors.initials: G
authors.lastname: Morace
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fadda
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Blasi
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000235:genetics / Q000276:immunology*; D005656:Fungal Proteins / Q000235:genetics / Q000276:immunology*; D017353:Gene Deletion; D018628:Gene Dosage; D017628:Microglia / Q000276:immunology* / Q000382:microbiology*; D010588:Phagosomes / Q000276:immunology* / Q000382:microbiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D005656:Fungal Proteins