The interaction between Candida albicans and cells of the innate immune system is a key determinant of
disease progression. Transcriptional profiling has revealed that C. albicans has a complex response to phagocytosis, much of which is similar to
carbon starvation. This suggests that nutrient limitation is a significant stress in vivo, and we have shown that
glyoxylate cycle mutants are less virulent in mice. To examine whether other aspects of
carbon metabolism are important in vivo during an
infection, we have constructed strains lacking FOX2 and FBP1, which encode key components of
fatty acid beta-oxidation and gluconeogenesis, respectively. As expected, fox2Delta mutants failed to utilize several
fatty acids as
carbon sources. Surprisingly, however, these mutants also failed to grow in the presence of several other
carbon sources, whose assimilation is independent of beta-oxidation, including
ethanol and
citric acid. Mutants lacking the
glyoxylate enzyme ICL1 also had more severe
carbon utilization phenotypes than were expected. These results suggest that the regulation of alternative
carbon metabolism in C. albicans is significantly different from that in other fungi. In vivo, fox2Delta mutants show a moderate but significant reduction in virulence in a mouse model of disseminated
candidiasis, while disruption of the
glyoxylate cycle or gluconeogenesis confers a severe attenuation in this model. These data indicate that C. albicans often encounters
carbon-poor conditions during growth in the host and that the ability to efficiently utilize multiple nonfermentable
carbon sources is a virulence determinant. Consistent with this in vivo requirement, C. albicans uniquely regulates
carbon metabolism in a more integrated manner than in Saccharomyces cerevisiae, such that defects in one part of the machinery have wider impacts than expected. These aspects of alternative
carbon metabolism may then be useful as targets for therapeutic intervention.