Niche-specific regulation of central metabolic pathways in a fungal pathogen

Abstract

SummaryTo establish an infection, the pathogen Candida albicans must assimilate carbon and grow in its mammalian host. This fungus assimilates six-carbon compounds via the glycolytic pathway, and twocarbon compounds via the glyoxylate cycle and gluconeogenesis. We address a paradox regarding the roles of these central metabolic pathways in C. albicans pathogenesis: the glyoxylate cycle is apparently required for virulence although glyoxylate cycle genes are repressed by glucose at concentrations present in the bloodstream. Using GFP fusions, we confirm that glyoxylate cycle and gluconeogenic genes in C. albicans are repressed by physiologically relevant concentrations of glucose, and show that these genes are inactive in the majority of fungal cells infecting the mouse kidney. However, these pathways are induced following phagocytosis by macrophages or neutrophils. In contrast, glycolytic genes are not induced following phagocytosis and are expressed in infected kidney. Mutations in all three pathways attenuate the virulence of this fungus, highlighting the importance of central carbon metabolism for the establishment of C. albicans infections. We conclude that C. albicans displays a metabolic program whereby the glyoxylate cycle and gluconeogenesis are activated early, when the pathogen is phagocytosed by host cells, while the subsequent progression of systemic disease is dependent upon glycolysis.

Polyamine biosynthesis and transport mechanisms are crucial for fitness and pathogenesis of Streptococcus pneumoniae

“…Recently, a growing body of literature has alluded to the role of basic metabolites and carbon metabolic pathways in the overall growth, fitness and virulence of bacterial pathogens (Barelle et al, 2006;Muñoz-Elías & McKinney, 2005;Naderer et al, 2006;Shelburne et al, 2008;Tchawa Yimga et al, 2006). In this study a similar degree of attenuation was seen for both transport and biosynthesis mutants during nasopharyngeal colonization, suggesting that genetic deficiencies affecting the availability of certain polyamines are equally detrimental to successful mucosal colonization.…”

Preferential transcription of Paracoccidioides brasiliensis genes: host niche and time-dependent expression

“…In liver, P. brasiliensis Pb01 cells induced genes associated with sugar utilization and alcohol fermentation, such as acylphosphatase (E.C.3.6.1.7), quinoprotein alcohol dehydrogenase (E.C.1.1.99.8) and glucokinase (E.C.2.7.1.2). Of special note, and corroborating our data, the predominance of glycolytic metabolism in Candida albicans infecting mouse kidney (Barelle et al 2006) has been described. The over-expression of carbohydrate metabolism enzymes and overproduction of ethanol suggest that this metabolic pathway could be particularly relevant during liver infection because of the abundant glucose in the host milieu, as described by Costa et al (2007).…”

Evolution inCandida albicansPopulations During a Single Passage Through a Mouse Host

“…Immediately after C. albicans is introduced into the mouse host, population sizes dramatically decline in the bloodstream and kidneys and subsequently expand exponentially in the kidney, causing renal failure and death (Odds et al 2000;MacCallum and Odds 2004). Because log growth is density independent, the results suggest that the slower growth trajectory characteristic of in vivo populations is less likely a result of direct competition among C. albicans cells and more likely a result of higher cell mortality due to the host immune response or slower cell division due to nutrient limitations (Barelle et al 2006;Bernardis et al 2007). The linear growth rate of pseudohyphal and hyphal cells (Hausauer et al 2005) may also contribute to slower population growth in the in vivo environment.…”