| Cryptococcus neoformans is an environmental fungus that is able to cause potentially fatal disease in immunocompromised patients. During the course of infection, C. neoformans is able to successfully evade the innate immune system, eventually disseminating throughout the host tissues and finally causing morbid meningoencephalitis. The primary means of defense by the innate immune system is the reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by professional phagocytes. To survive in the host, C. neoformans---which can survive and replicate within macrophages---requires defensive mechanisms against the toxic ROS and RNS. In this study, we investigated the changes that occur at the genomic and proteomic levels in C. neoformans in response to oxidative stress. We also investigated the pentose phosphate pathway and NADP+-dependent isocitrate dehydrogenase as potential sources of NADPH, the reductive cofactor important for the function of many of the antioxidant proteins and pathways known to be essential for resistance to stress and for virulence.;We found that the substantial response to oxidative stress in the C. neoformans transcriptome is not mirrored in the proteome, where we found very few changes in response to oxidative stress. We also found that unlike in many other systems, the oxidative phase of the pentose phosphate pathway is not important for stress resistance. Instead, NADP+-dependent isocitrate dehydrogenase is important for resistance to nitrosative stress. Our findings provide implications for how adaptation of C. neoformans to its environmental niche affects interactions with the mammalian innate immune system. |
