A novel genetic circuitry governing hypoxic metabolic flexibility, commensalism and virulence in the fungal pathogen Candida albicans

Abstract

Inside the human host, the pathogenic yeast Candida albicans colonizes predominantly oxygen-poor niches such as the gastrointestinal and vaginal tracts, but also oxygen-rich environments such as cutaneous epithelial cells and oral mucosa. This suppleness requires an effective mechanism to reprogram reversibly the primary metabolism in response to oxygen variation. Here, we have uncovered that Snf5, a subunit of SWI/SNF chromatin remodeling complex, is a major transcriptional regulator that links oxygen status to the metabolic capacity of C. albicans. Snf5 and other subunits of SWI/SNF complex were required to activate genes of alternative carbon utilization and other carbohydrates related process specifically under hypoxia. snf5 mutant exhibited an altered metabolome reflecting that SWI/SNF plays an essential role in maintaining metabolic homeostasis and carbon flux in C. albicans under hypoxia. Snf5 was necessary to activate the transcriptional program linked to both commensal and invasive growth. Accordingly, snf5 was unable to maintain its growth in the stomach, the cecum and the colon of mice. snf5 was also avirulent as it was unable to invade Galleria larvae or to cause damage to human enterocytes and murine macrophages. Among candidates of signaling pathways in which Snf5 might operate, phenotypic analysis revealed that mutants of Ras1-cAMP-PKA pathway, as well as mutants of Yak1 and Yck2 kinases exhibited a similar carbon flexibility phenotype as did snf5 under hypoxia. Genetic interaction analysis indicated that the adenylate cyclase Cyr1, a key component of the Ras1-cAMP pathway, but not Ras1, interacted genetically with Snf5. Our study yielded unprecedented insight into the oxygen-sensitive regulatory circuit that control metabolic flexibility, stress, commensalism and virulence in C. albicans.Author SummaryA critical aspect of eukaryotic cell fitness is the ability to sense and adapt to variations in oxygen concentrations in their local environment. Hypoxia leads to a substantial remodeling of cell metabolism and energy homeostasis, and thus, organisms must develop an effective regulatory mechanism to cope with oxygen depletion. Candida albicans is an opportunistic yeast that is the most prevalent human fungal pathogens. This yeast colonizes diverse niches inside the human host with contrasting carbon sources and oxygen concentrations. While hypoxia is the predominant conditions that C. albicans encounters inside most of the niches, the impact of this condition on metabolic flexibility, a major determinant of fungal virulence, was completely neglected. Here, we uncovered that the chromatin remodelling complex SWI/SNF is master regulatory circuit that links oxygen status to a broad spectrum of carbon utilization routes. Snf5 was essential for the maintenance of C. albicans as a commensal and also for the expression of its virulence. The oxygen-sensitive regulators identified in this work provide a framework to comprehensively understand the virulence of human fungal pathogens and represent a therapeutic value to fight fungal infections.

Catch the wave: Metabolomic analyses in human pathogenic fungi

“…Metabolomic approaches brought insight into C . albicans virulence mechanisms, antifungal effects, and biofilm growth [ 6 , 13 , 18 , 21 – 25 , 28 – 33 , 35 – 39 ]. Although one study focused on secreted metabolites and biomarkers in C .…”

“…A combination of transcriptomic and metabolomic approaches defined the importance of C . albicans Snf5, a subunit of the SWI/SNF chromatin remodeling complex, in controlling metabolic flexibility and fungal fitness specifically under hypoxia [ 33 ].…”

The RSC (Remodels the Structure of Chromatin) complex of Candida albicans shows compositional divergence with distinct roles in regulating pathogenic traits

“…GSEA was performed using standard parameters [ 9 ]. Gene lists were filtered as mentioned for GO analysis above.…”

“…The functions of the CRCs in relation to the pathogenic attributes of C . albicans are primarily known from the studies on the SWI/SNF complex [ 9 – 12 ]. However, how other CRCs feed into these pathways to regulate C .…”

Targeting SWI/SNF metabolic vulnerabilities in cancer

“…Interestingly, a study by Burgain and colleagues demonstrated that Candida albicans (C. albicans) with Snf5 (also called SMARCB1) mutations cannot grow on alternative carbon sources in hypoxia. However, the mutants can grow normally on fermentable carbohydrates like glucose and fructose (26). The authors determined that Snf5 is required for survival in hypoxia via regulation of carbon flexibility, ultimately concluding that the SWI/SNF complex is a master regulator that connects the oxygen-sensing machinery with carbon utilization in C. albicans.…”