The virulence factor urease and its unexplored role in the metabolism of Cryptococcus neoformans

Cryptococcal urease is believed to be important for the degradation of exogenous urea that the yeast encounters both in its natural environment and within the human host. Endogenous urea produced by the yeast's own metabolic reactions, however, may also serve as a substrate for the urease enzyme. Using wild-type, urease-deletion mutant and urease-reconstituted strains of Cryptococcus neoformans H99, we studied reactions located up- and downstream from endogenous urea. We demonstrated that urease is important for cryptococcal growth and that, compared to nutrient-rich conditions at 26°C, urease activity is higher under nutrient-limited conditions at 37°C. Compared to cells with a functional urease enzyme, urease-deficient cells had significantly higher intracellular urea levels and also showed more arginase activity, which may act as a potential source of endogenous urea. Metabolic reactions linked to arginase were also affected, since urease-positive and urease-negative cells differed with respect to agmatinase activity, polyamine synthesis, and intracellular levels of proline and reactive oxygen species. Lastly, urease-deficient cells showed higher melanin levels at 26°C than wild-type cells, while the inverse was observed at 37°C. These results suggest that cryptococcal urease is associated with the functioning of key metabolic pathways within the yeast cell

Human genetic susceptibility to Candida infections

Item does not contain fulltextInfections with Candida spp. have different manifestations in humans, ranging from mucosal to bloodstream and deep-seated disseminated infections. Immunocompromised patients have increased susceptibility to these types of infections, due to reduced capacity to elicit effective innate or adaptive immunity. In addition, rare and common genetic variants in the human genome have been identified that influence susceptibility to Candida infections. Genetic determinants of primary immunodeficiencies leading to chronic mucocutaneous candidiasis have been reported, and polymorphisms in genes that are known to be involved in anti-Candida host defense are associated with increased susceptibility to systemic infection. These findings have greatly increased our understanding of pathways important for anti-Candida defense in humans, and patterns of prevalence of Candida infections. In addition, these pathways may offer novel therapeutic targets for treatment. This review provides an overview of the current insights in genetic susceptibility to Candida infections and their consequences for the immune response against Candida