Glutathione-mediated redox regulation in Cryptococcus neoformans impacts virulence.
Braydon BlackLeandro Buffoni Roque da SilvaGuanggan HuXianya QuDaniel F Q SmithArmando Alcázar MagañaLinda C HorianopoulosMélissa CazaRodgoun AttarianLeonard J FosterArturo CasadevallJames W KronstadPublished in: Nature microbiology (2024)
The fungal pathogen Cryptococcus neoformans is well adapted to its host environment. It has several defence mechanisms to evade oxidative and nitrosative agents released by phagocytic host cells during infection. Among them, melanin production is linked to both fungal virulence and defence against harmful free radicals that facilitate host innate immunity. How C. neoformans manipulates its redox environment to facilitate melanin formation and virulence is unclear. Here we show that the antioxidant glutathione is inextricably linked to redox-active processes that facilitate melanin and titan cell production, as well as survival in macrophages and virulence in a murine model of cryptococcosis. Comparative metabolomics revealed that disruption of glutathione biosynthesis leads to accumulation of reducing and acidic compounds in the extracellular environment of mutant cells. Overall, these findings highlight the importance of redox homeostasis and metabolic compensation in pathogen adaptation to the host environment and suggest new avenues for antifungal drug development.
Keyphrases
- escherichia coli
- pseudomonas aeruginosa
- biofilm formation
- staphylococcus aureus
- induced apoptosis
- antimicrobial resistance
- candida albicans
- cell cycle arrest
- single cell
- oxidative stress
- endoplasmic reticulum stress
- mass spectrometry
- cell death
- electron transfer
- bone marrow
- signaling pathway
- mesenchymal stem cells
- cell proliferation
- pi k akt
- ionic liquid
- wild type