Immune Response-Associated Cytokines Modulate the Phenotypic Plasticity of Cryptococcus neoformans

Cryptococcus neoformans (Cn) is considered an opportunistic pathogen that has become increasingly relevant to human health since the HIV epidemic in the 1980s. Currently, it ranks first on the World Health Organization’s list of critical priority fungal pathogens. It is estimated to be responsible for approximately 200,000 deaths annually, mainly associated with cryptococcal meningitis, the most severe form of cryptococcosis. Studies have shown that this fungus exhibits virulence factors and sophisticated immune evasion mechanisms that vary according to the type of immune response triggered in the host. In this context, this study aimed to investigate aspects of the phenotypic plasticity of Cryptococcus neoformans yeast cells when exposed to different immunological profiles. For this purpose, H99 strain yeast cells were cultured in the presence or absence of IL-4 or IFNγ. From these treated yeast cells, cell body diameter, capsule thickness, budding frequency and growth on solid medium under different dilutions and temperatures were evaluated. In addition, infected RAW 264.7 macrophages were analyzed by flow cytometry to assess the expression of arginase-1 and iNOS markers. Also, the phagocytosis frequency and  the dosage of reactive species of nitrogen was made. At the end of the study, it was observed that the fungus adapts to both types of immune responses, modulates phagocytic capacity and influences the macrophage polarization profile. These findings reinforce the high phenotypic plasticity of C. neoformans in response to different immunological microenvironments.