Histone deacetylases inhibitors effects on Cryptococcus neoformans major virulence phenotypes

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.