Isocitrate Dehydrogenase Is Important for Nitrosative Stress Resistance in Cryptococcus neoformans, but Oxidative Stress Resistance Is Not Dependent on Glucose-6-Phosphate Dehydrogenase

Abstract

The opportunistic intracellular fungal pathogen Cryptococcus neoformans depends on many antioxidant and denitrosylating proteins and pathways for virulence in the immunocompromised host. These include the glutathione and thioredoxin pathways, thiol peroxidase, cytochrome c peroxidase, and flavohemoglobin denitrosylase. All of these ultimately depend on NADPH for either catalytic activity or maintenance of a reduced, functional form. The need for NADPH during oxidative stress is well established in many systems, but a role in resistance to nitrosative stress has not been as well characterized. In this study we investigated the roles of two sources of NADPH, glucose-6-phosphate dehydrogenase (Zwf1) and NADP ؉ -dependent isocitrate dehydrogenase (Idp1), in production of NADPH and resistance to oxidative and nitrosative stress. Deletion of ZWF1 in C. neoformans did not result in an oxidative stress sensitivity phenotype or changes in the amount of NADPH produced during oxidative stress compared to those for the wild type. Deletion of IDP1 resulted in greater sensitivity to nitrosative stress than to oxidative stress. The amount of NADPH increased 2-fold over that in the wild type during nitrosative stress, and yet the idp1⌬ strain accumulated more mitochondrial damage than the wild type during nitrosative stress. This is the first report of the importance of Idp1 and NADPH for nitrosative stress resistance.

Global Transcriptome Profile of Cryptococcus neoformans during Exposure to Hydrogen Peroxide Induced Oxidative Stress

“…Previous studies demonstrated that neither the ZWF1 mRNA nor protein levels were altered during nitrosative stress in C. neoformans. Consistent with this deletion of ZWF1 gene in C. neoformans did not increase their sensitivity to either oxidative or nitrosative stress [72], [77]. These are consistent with our present observations that pentose phosphate pathway does not participate in peroxide induced oxidative stress resistance in C. neoformans .…”

The CovS/CovR Acid Response Regulator Is Required for Intracellular Survival of Group B Streptococcus in Macrophages

“…GBS shows an increased tolerance to hydrogen peroxide stress in comparison with the nonpathogenic organism L. lactis, which is highly sensitive to the chemical. However, previous data suggest that 14 mM H 2 O 2 accurately reflects the ROS conditions inside an activated alveolar macrophage (6), and this concentration is sufficient to kill GBS in vitro (Fig. 4A).…”

“…that the associated carotenoid pigment is required for intracellular survival due to its ability to scavenge free radicals (31). We have shown that GBS is sensitive in vitro to levels of hydrogen peroxide that are thought to be physiologically relevant in activated phagocytic cells (6); however, the inhibition of ROS through the NADPH oxidase does not affect intracellular survival of wild-type GBS. This would support our findings and previous work suggesting that GBS-containing phagosomes fail to undergo a full oxidative burst when the organism has been ingested in the absence of opsonizing antibody (10,14).…”

Identification of Differentially Expressed Proteins from Leishmania amazonensis Associated with the Loss of Virulence of the Parasites

“…In this context, phosphatase 1 guanyltransferase mannose is involved in oxidative stress in yeast [93], while isocitrate dehydrogenase is involved in cellular stress in Cryptococcus neoformans [94]. The glucose regulated protein 78 kDa is a membrane protein that is up-regulated in conditions of cellular stress and that can lead to cell cycle arrest [95].…”