TY - JOUR
T1 - Fluconazole alters the polysaccharide capsule of cryptococcus gattii and leads to distinct behaviors in murine cryptococcosis
AU - Santos, Julliana Ribeiro Alves
AU - Holanda, Rodrigo Assunção
AU - Frases, Susana
AU - Bravim, Mayara
AU - Araujo, Glauber De S.
AU - Santos, Patrícia Campi
AU - Costa, Marliete Carvalho
AU - Ribeiro, Maira Juliana Andrade
AU - Ferreira, Gabriella Freitas
AU - Baltazar, Ludmila Matos
AU - Miranda, Aline Silva
AU - Oliveira, Danilo Bretas
AU - Santos, Carolina Maria Araújo
AU - Fontes, Alide Caroline Lima
AU - Gouveia, Ludmila Ferreira
AU - Resende-Stoianoff, Maria Aparecida
AU - Abrahão, Jonatas Santos
AU - Teixeira, Antonio Lúcio
AU - Paixão, Tatiane Alves
AU - Souza, Danielle G.
AU - Santos, Daniel Assis
N1 - Publisher Copyright:
© 2014 Santos et al.
PY - 2014/11/13
Y1 - 2014/11/13
N2 - Cryptococcus gattii 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 C. gattii was cultivated in high fluconazole concentrations and developed decreased drug susceptibility. This phenotype was named L27/01F, that was less virulent than L27/01 in mice. The physical, structural and electrophoretic properties of the PS capsule of L27/01F were altered by fluconazole. L27/ 01F presented lower antiphagocytic properties and reduced survival inside macrophages. The L27/01F 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/ 01F 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 L27/01F. Our results suggest that stress to fluconazole alters the capsule of C. gattii and influences the clinical manifestations of cryptococcosis.
AB - Cryptococcus gattii 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 C. gattii was cultivated in high fluconazole concentrations and developed decreased drug susceptibility. This phenotype was named L27/01F, that was less virulent than L27/01 in mice. The physical, structural and electrophoretic properties of the PS capsule of L27/01F were altered by fluconazole. L27/ 01F presented lower antiphagocytic properties and reduced survival inside macrophages. The L27/01F 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/ 01F 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 L27/01F. Our results suggest that stress to fluconazole alters the capsule of C. gattii and influences the clinical manifestations of cryptococcosis.
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U2 - 10.1371/journal.pone.0112669
DO - 10.1371/journal.pone.0112669
M3 - Article
C2 - 25392951
AN - SCOPUS:84911908514
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 11
M1 - 2014
ER -