Histone deacetylases inhibitors effects on Cryptococcus neoformans major virulence phenotypes
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Published on: February 27, 2018
Fabiana As Brandão1, Lorena S Derengowski1, Patrícia Albuquerque2,3
1a Laboratory of Molecular Biology; Department of Cell Biology; Institute of Biological Sciences; University of Brasilia ; Brasilia , DF , Brazil.
Abstract:
Cryptococcus neoformans undergoes phenotypical changes during host infection in order to promote persistence and survival. Studies have demonstrated that such adaptations require alterations in gene transcription networks by distinct mechanisms. Drugs such as the histone deacetylases inhibitors (HDACi) Sodium Butyrate (NaBut) and Trichostatin A (TSA) can alter the chromatin conformation and have been used to modulate epigenetic states in the treatment of diseases such as cancer. In this work, we have studied the effect of NaBut and TSA on the expression of C. neoformans major virulence phenotypes and on the survival rate of an animal model infected with drugs-treated yeasts. Both drugs affected fungal growth at 37°C more intensely than at 30°C; nonetheless, drugs did not affect cell viability at the concentrations we studied. HDACi also provoked the reduction of the fungal capsule expansion. Phospholipases enzyme activity decreased; mating process and melanin synthesis were also affected by both inhibitors. NaBut led to an increase in the population of cells in G2/M. Treated yeast cells, which were washed in order to remove the drugs from the culture medium prior to the inoculation in the Galleria mellonela infection model, did not cause significant difference at the host survival curve when compared to non-treated cells. Overall, NaBut effects on the impairment of C. neoformans main virulence factors were more intense and stable than the TSA effects.
Insights
Histone deacetylase inhibitors (HDACi) like Sodium Butyrate (NaBut) and Trichostatin A (TSA) reduced Cryptococcus neoformans virulence factors, including capsule expansion and phospholipase activity. However, these HDACi did not improve survival in a Galleria mellonela infection model.
Area of Science:
- Mycology
- Epigenetics
- Infectious Diseases
Background:
- Cryptococcus neoformans exhibits phenotypic plasticity during infection, essential for survival.
- Epigenetic modifications, such as those influenced by histone deacetylase inhibitors (HDACi), play a role in regulating fungal virulence.
- HDACi, including Sodium Butyrate (NaBut) and Trichostatin A (TSA), are known to modulate chromatin structure and gene expression.
Purpose of the Study:
- To investigate the impact of NaBut and TSA on key virulence factors of Cryptococcus neoformans.
- To evaluate the effect of HDACi treatment on the survival rate of an animal model infected with C. neoformans.
Main Methods:
- Treatment of C. neoformans with NaBut and TSA at different temperatures (30°C and 37°C).
- Assessment of fungal growth, cell viability, capsule expansion, phospholipase activity, melanin synthesis, and cell cycle progression (G2/M phase).
- Infection of Galleria mellonela model with drug-treated C. neoformans and monitoring of host survival.
Main Results:
- Both NaBut and TSA inhibited fungal growth more significantly at 37°C than 30°C, without affecting cell viability.
- HDACi treatment led to reduced fungal capsule expansion, decreased phospholipase activity, and impaired mating and melanin synthesis.
- NaBut treatment resulted in an increased population of cells in the G2/M phase.
- Yeast cells treated with HDACi, even after washing to remove residual drugs, did not show improved survival rates in the Galleria mellonela model compared to untreated cells.
- NaBut demonstrated more potent and stable inhibition of C. neoformans virulence factors than TSA.
Conclusions:
- NaBut and TSA effectively impair major virulence factors of Cryptococcus neoformans, suggesting a role for epigenetic regulation in fungal pathogenesis.
- Despite the observed reduction in virulence factors, HDACi treatment did not translate to enhanced host survival in the Galleria mellonela model.
- NaBut appears to be a more effective HDAC inhibitor for targeting C. neoformans virulence compared to TSA.
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