Cryptococcus gattii: estudo dos mecanismos genéticos de adaptação aos agroquímicos e da coinfecção com Strongyloides venezuelensis

Abstract

Cryptococcus gattii (Cg) is one of the main etiological agents of cryptococcosis, a systemic mycosis that affects the lungs and the central nervous system. Cg can be found in the environment associated with plants and, at the same time, the use of agrochemicals has been intensified in recent years. In previous studies, exposure to the environmental antifungal agents tebuconazole (TBZ) and pyraclostrobin (PCT) increased the tolerance of the R265 strain to fluconazole (FCZ). This was also observed in the L24/01 strain exposed to benomyl (BEN), but it became more virulent. In the first chapter of this thesis, genome sequences of these strains were used in order to understand the genetic mechanisms of adaptation of the fungus to agrochemicals. It was observed that structural changes in different genes conferred greater plasticity on strains exposed to antifungal agents, allowing the growth of these strains at higher concentrations of agrochemicals, in addition to promoting a cross-resistance effect with the clinically used antifungal drug FCZ. Another point addressed in this thesis was the study of co-infection between Cg and the parasite Strongyloides venezuelensis (Sv), which causes an intestinal disease associated with a lack of basic sanitation. A common factor between cryptococcosis and strongyloidiasis is a higher prevalence in Africa and tropical regions, including Brazil, and that during the life cycle of the parasites, passage through the host's lung occurs, which could contribute to the occurrence of co-infections of the parasite with Cg. However, to date there are no studies of infections with the aforementioned organisms. Therefore, the influence of Sv infection on the progression of murine cryptococcosis caused by Cg was evaluated. Macrophage stimulation with Sv antigens resulted in greater intracellular fungal proliferation. Mice infected with Sv before Cg showed increased morbidity, mortality, fungal burden in the alveolar space, and lung parenchyma. This phenotype was accompanied by increased eosinophil recruitment, increased IL-4, and decreased IL-1β. These results suggest that the co-infection with Strongyloides promotes an IL-4-mediated change in the host response to the Th2 type, promoting the spread of the fungus and greater damage to the host.