Heteroresistance to Itraconazole Alters the Morphology and Increases the Virulence of Cryptococcus gattii |
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| Authors: | Gabriella Freitas Ferreira Julliana Ribeiro Alves Santos Marliete Carvalho da Costa Rodrigo Assun??o de Holanda ?ngelo Márcio Leite Denadai Gustavo José Cota de Freitas áquila Rodrigues Costa Santos Priscila Batista Tavares Tatiane Alves Paix?o Daniel Assis Santos |
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| Affiliation: | aDepartamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Pampulha, Belo Horizonte, Minas Gerais, Brazil;bDepartamento de Farmácia, Universidade Federal de Juiz de Fora–Campus Governador Valadares, Centro, Governador Valadares, Minas Gerais, Brazil;cUniversidade Vale do Rio Doce, Universitário, Governador Valadares, Minas Gerais, Brazil |
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| Abstract: | Cryptococcus gattii is the main etiological agent of cryptococcosis in immunocompetent individuals. The triazole drug itraconazole is one of the antifungals used to treat patients with cryptococcosis. Heteroresistance is an adaptive mechanism to counteract the stress of increasing drug concentrations, and it can enhance the ability of a microorganism to survive under antifungal pressure. In this study, we evaluated the ability of 11 C. gattii strains to develop itraconazole heteroresistance. Heteroresistant clones were analyzed for drug susceptibility, alterations in cell diameter, capsule properties, and virulence in a murine model. Heteroresistance to itraconazole was intrinsic in all of the strains analyzed, reduced both the capsule size and the cell diameter, induced molecular heterogeneity at the chromosomal level, changed the negatively charged cells, reduced ergosterol content, and improved the antioxidant system. A positive correlation between surface/volume ratio of original cells and the level of heteroresistance to itraconazole (LHI) was observed in addition to a negative correlation between capsule size of heteroresistant clones and LHI. Moreover, heteroresistance to itraconazole increased the engulfment of C. gattii by macrophages and augmented fungal proliferation inside these cells, which probably accounted for the reduced survival of the mice infected with the heteroresistant clones and the higher fungal burden in lungs and brain. Our results indicate that heteroresistance to itraconazole is intrinsic and increases the virulence of C. gattii. This phenomenon may represent an additional mechanism that contributes to relapses of cryptococcosis in patients during itraconazole therapy. |
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