Glutathione metabolism impacts fungal virulence by modulating the redox environment

Pathogens must overcome the hostile conditions of their hosts to survive, proliferate and cause disease. The fungal pathogen Cryptococcus neoformans is particularly adept at mitigating challenges in the host environment and has developed an arsenal of defense mechanisms to evade oxidative and nitrosative agents released by phagocytic cells during infection. Among these mechanisms, melanin production is crucially linked to both fungal virulence and defense against harmful free radicals that facilitate host innate immunity and clearance of invading pathogens. Here, we employed comparative global metabolomics to demonstrate that metabolism of the antioxidant glutathione (GSH) is inextricably linked to redox-active processes that facilitate melanin production, and that genetic perturbations in GSH biosynthesis affect fungal growth and virulence in a murine model of cryptococcosis. Furthermore, we show that disruption of GSH biosynthesis leads to overaccumulation of reducing and acidic compounds in the extracellular environment of mutant cells. These changes not only impacted melanin formation but also influenced titan cell and urease production as well as survival in macrophages. 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.