Avaliação de fatores de resistência ao fluconazol em modelo murino de criptococose causada por Cryptococcus gattii

Abstract

Cryptococcosis is an invasive infection caused by yeast-like fungus of the genera Cryptococcus spp., which can show up as an asymptomatic pulmonary colonization, even as meningitis or disseminated disease. Cryptococcus gattii, typically found in tropical and subtropical climates, is usually cause disease in immunocompetent hosts. The polysaccharide capsule is important for the survival of the microorganism in the environment and in the host and is considered an important virulence factor. The availability of antifungal therapy for this disease is relatively small, and providing some toxicity, while the incidence of infections caused by resistant strains increased. Thus, the objective of this study is to evaluate the development of resistance to fluconazole by C. gattii during infection in a murine model, the effects on the progression of cryptococcosis in immunosuppression model, and the proteins identification in C. gattii strain after infection. Disease progression was assessed by the behavioral analysis, quantification of CFU in the organs and expression of type I interferons. After recovery of fungal colonies was evaluated the expression of genes encoding efflux pumps, ERG11 gene and the genes responsible for the synthesis and assembly of polysaccharide capsule. Recovered colonies proteins for mass spectrometric analysis were also extracted. The immunosuppression model was induced by dexamethasone. In the present study, the subdose of fluconazole alter the virulence factors of the fungus, decreases the susceptibility to fluconazole, modifying the host inflammatory response and increases the morbidity of mice infected with C. gattii. Treatment with fluconazole even in immunosuppressed host, increases survival of it. And that immunosuppression contributed to a decrease in yeast migration to the central nervous system (CNS) in animals, probably due to lower phagocytic activity and reduced fungicidal activity of macrophages from such animals. In conclusion, we supply new perspectives on treatment with fluconazole in cryptococcosis. Knowledge of the way by which the factors of resistance to fluconazole affect the virulence of C. gattii and the host immune response is critical to understand the clinical impact of antifungal resistance in cryptococcosis. Due to the increasing number of cases and deaths by cryptococcosis, studies involving C. gattii and address the factors that antifungal resistance should be a research priority.