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A subdose of fluconazole alters the virulence of Cryptococcus gattii during murine cryptococcosis and modulates type
Alide Caroline Lima Fontes1, Danilo Bretas Oliveira2,3, Juliana Ribeiro Alves Santos1,4
1Laboratório de Micologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
Abstract:
Cryptococcosis is an invasive infection caused by yeast-like fungus of the genera Cryptococcus spp. The antifungal therapy for this disease provides some toxicity and the incidence of infections caused by resistant strains increased. Thus, we aimed to assess the consequences of fluconazole subdoses during the treatment of cryptococcosis in the murine inflammatory response and in the virulence factors of Cryptococcus gattii. Mice infected with Cryptococcus gattii were treated with subdoses of fluconazole. We determined the behavior of mice and type 1 interferon expression during the treatment; we also studied the virulence factors and susceptibility to fluconazole for the colonies recovered from the animals. A subdose of fluconazole prolonged the survival of mice, but the morbidity of cryptococcosis was higher in treated animals. These data were linked to the increase in: (i) fluconazole minimum inhibitory concentration, (ii) capsule size and (iii) melanization of C. gattii, which probably led to the increased expression of type I interferons in the brains of mice but not in the lungs. In conclusion, a subdose of fluconazole altered fungal virulence factors and susceptibility to this azole, leading to an altered inflammatory host response and increased morbidity.
Insights
Subdoses of fluconazole prolonged survival in mice with cryptococcosis but increased fungal virulence and host inflammatory response, leading to higher morbidity. This highlights risks of altered antifungal dosing in invasive fungal infections.
Area of Science:
- Mycology
- Infectious Diseases
- Immunology
Background:
- Cryptococcosis is a serious fungal infection often treated with azoles.
- Antifungal drug toxicity and rising resistance necessitate treatment evaluation.
- Fluconazole resistance and altered virulence factors are clinical concerns.
Purpose of the Study:
- To investigate the impact of fluconazole subdoses on Cryptococcus gattii virulence.
- To assess the effects on murine inflammatory responses during cryptococcosis treatment.
- To determine changes in fungal susceptibility and virulence post-subdose treatment.
Main Methods:
- Mice infected with Cryptococcus gattii were treated with fluconazole subdoses.
- Murine behavior, survival, and type I interferon expression were monitored.
- Virulence factors (capsule size, melanization) and fluconazole susceptibility of recovered fungi were analyzed.
Main Results:
- Fluconazole subdoses prolonged mouse survival but increased overall morbidity.
- Recovered Cryptococcus gattii exhibited increased fluconazole minimum inhibitory concentration.
- Enhanced fungal virulence was observed, including larger capsules and increased melanization.
- Type I interferon expression increased in mouse brains, correlating with altered fungal factors.
Conclusions:
- Fluconazole subdoses can promote Cryptococcus gattii virulence and reduce susceptibility.
- Altered fungal virulence factors contribute to increased host inflammatory responses and morbidity.
- Suboptimal antifungal dosing poses significant risks in managing invasive fungal infections.
