Morphogenesis of Candida albicans

 

Candida albicans is a human commensal fungus that can be isolated from approximately 70% of the healthy population. In the majority of cases C. albicans is harmless, however, if the person is immunocompromised, it can be an opportunistic pathogen. C. albicans is the fourth leading cause of nosocomial bloodstream infections, with an attributable mortality of 37-44% in severely immunocompromised patients

C. albicans have the remarkable ability to grow in several distinct morphological forms: yeast, hyphae, and pseudohyphae, according to environmental conditions. The ability to switch rapidly from yeast to filamentous growth or vice versa in response to certain environmental cues is considered to be a critical virulence factor for this fungus. We aim to unravel the metabolic pathways essential for C. albicans morphogenesis using metabolomics and metabolic flux analysis.

C. albicans is a polymorphic fungus that has the remarkable ability to rapidly switch between yeast and hyphal forms (Fig. 1) in response to various environmental factors (e.g. quorum sensing molecules). This morphological transition is considered to be a critical virulence factor of this fungus. The metabolic mechanisms that recognize environmental signals and promote the morphological changes at a system level, however, remain unclear. In this study, we investigated the metabolic changes during the morphogenesis of C. albicans under laboratory conditions using metabolomics (Fig 2) and isotope-labelling experiments. Our results demonstrated that 16 metabolic pathways involved in the central carbon metabolism were significantly up-regulated when C. albicans changed from yeast to hyphal form (Fig 3), whilst 11 metabolic pathways were downregulated when hyphal formation was suppressed by specific quorum sensing molecules (farnesol and phenylethyl alcohol). Combining the results from isotope-labelling experiment with metabolomics data, a final shortlist of 2 metabolic pathways was obtained. These pathways highlighted the important role of NADP+/NADPH in the global regulation of C. albicans morphogenesis. The importance of each pathway on the morphological switch of C. albicans is being validated by gene knockout mutagenesis (Fig 4).

 

Fig 1. C. albicans transfoms rapidly from yeast to cluster of hyphae after three hours of colonisation. A) yeast form, b) hyphal form, and C) clusters of hyphae.


Fig 2. The metabolomic platform we used to study the metabolic changes of C. albicans during morphogenesis.

 

Fig 3. Heatmap show that 16 metabolic pathway appear significantly up-regulated when C. albicans transforms from yeast to hyphal forms.

Fig 4. The SAT1 flipper gene knockout method that we used to validate our shortlisted metabolic pathways.

 

Related publications:

Han T-L, Tumanov S, Cannon RD, Villas-Boas SG (2013) Metabolic Response ofCandida albicans to Phenylethyl Alcohol under Hyphae-Inducing Conditions. PLoS ONE 8(8): e71364. doi:10.1371/journal.pone.0071364 >>>

Han, T.; Cannon, R.D.; Villas-Boas, S.G. 2012. The metabolic response of Candida albicans to farnesol under hyphae-inducing conditions. FEMs Yeast Research 12: 879 – 889. doi:10.1111/j.1567-1364.2012.00837.x >>>

Han, T.; Cannon, R.D.; Villas-Boas, S.G. 2012. Metabolome analysis during the morphological transition of Candida albicans. Metabolomics 8: 1204 – 1217. doi:10.1007/s11306-012-0416-6 >>>

Han, T.; Cannon, R.D.; Villas-Boas, S.G. 2011. The metabolic basis of Candida albicans morphogenesis and quorum sensing. Fungal Genetics & Biology 48: 747–763. doi:10.1016/j.fgb.2011.04.002 >>>

 

 

 

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