Candida albicans, a normal component of the mammalian gastrointestinal flora, causes most fungal infections in immunosuppressed patients. Candida is normally phagocytosed by macrophages and neutrophils. Neutropenic patients, deficient in these immune cells, are particularly susceptible to systemic candidiasis. Systematic studies of host–pathogen interactions, however, have been hampered by the lack of genetic tools in C. albicans. Recently, Lorenz applied genome-wide expression profiles of the related, non-pathogenic yeast Saccharomyces cerevisiae to obtain a signature of the events that take place in the fungus on ingestion by murine macrophages, and reported that the glyoxylate cycle is required for C. albicans virulence. Lorenz and colleagues were the first to demonstrate that genes encoding the glyoxylate cycle are required for virulence in fungus that can survive inside a macrophage.After subjecting a population of phagocytosed S. cerevisiae to whole-genome microarray analysis, the authors found that 11 of the 15 most highly induced S. cerevisiae genes after phagocytosis encoded proteins related to the glyoxylate cycle, through which two-carbon compounds are assimilated into the tricarboxylic acid (TCA) cycle. Three of the five glyoxylate cycle enzymes: isocitrate lyase (ICL1), malate synthase (MLS1) and malate dehydrogenase (MDH2), were upregulated by 22.7-, 22.5- and 15.7-fold, respectively. Furthermore, several genes functionally related to the glyoxylate cycle were also induced. The genes included those encoding acetyl coenzyme A (acetyl-CoA) synthase (ACS1) and fructose-1,6-bisphosphatase (FBP1), a central regulatory point in gluconeogenesis. Although the glyoxylate cycle and TCA share common reactions, it is striking that only the isozymes specialized for the glyoxylate cycle are induced. The expression of glyoxylate cycle enzymes did not change significantly in response to conditioned media, oxidative stress or contact with heat-killed macrophages. The results suggest that phogocytosis specifically upregulates the glyoxylate cycle. Finally, mutant strains of S. cerevisiae and C. albicans (Δicl1/Δicl1), which failed to use acetate or ethanol as expected, grew as well as their wild-type strains in rich medium, in exposure to a variety of in vivo stresses, including salt, heat shock, ethanol and oxidative stress. The mutant strains of C. albicans (Δicl1/Δicl1) were less virulent than their wild type in a mouse model of systemic candidiasis.The authors demonstrated that glyoxylate cycle is required but not sufficient for yeast pathogenesis. Their findings suggested that the phagolysosome is rich in fatty acids or their breakdown products (primarily acetyl-CoA), and acetylCoA can only be assimilated through the glyoxylate cycle, so the glyoxylate cycle is the only route to the synthesis of glucose in this environment. Because the enzymes of the glyoxylate cycle are not found in mammals, they are prime targets for antifungal agents [1xThe glyoxylate cycle is required for fungal virulence. Lorenz, M.C. et al. Nature. 2001; 412: 83–86Crossref | PubMed | Scopus (379)See all References[1].