Fluconazole Alters the Polysaccharide Capsule of <i>Cryptococcus gattii</i> and Leads to Distinct Behaviors in Murine Cryptococcosis

<div><p><i>Cryptococcus gattii</i> is an emergent human pathogen. Fluconazole is commonly used for treatment of cryptococcosis, but the emergence of less susceptible strains to this azole is a global problem and also the data regarding fluconazole-resistant cryptococcosis are scarce. We evaluate the influence of fluconazole on murine cryptococcosis and whether this azole alters the polysaccharide (PS) from cryptococcal cells. L27/01 strain of <i>C. gattii</i> was cultivated in high fluconazole concentrations and developed decreased drug susceptibility. This phenotype was named L27/01<b>_F</b>, that was less virulent than L27/01 in mice. The physical, structural and electrophoretic properties of the PS capsule of L27/01_F were altered by fluconazole. L27/01<b>_F</b> presented lower antiphagocytic properties and reduced survival inside macrophages. The L27/01<b>_F</b> did not affect the central nervous system, while the effect in brain caused by L27/01 strain began after only 12 hours. Mice infected with L27/01<b>_F</b> presented lower production of the pro-inflammatory cytokines, with increased cellular recruitment in the lungs and severe pulmonary disease. The behavioral alterations were affected by L27/01, but no effects were detected after infection with L27/01<b>_F</b>. Our results suggest that stress to fluconazole alters the capsule of <i>C. gattii</i> and influences the clinical manifestations of cryptococcosis.</p>