The Transcriptional Stress Response of Candida albicans to Weak Organic Acids

Abstract

Candida albicans is the most important fungal pathogen of humans, causing severe infections, especially in nosocomial and immunocompromised settings. However, it is also the most prevalent fungus of the normal human microbiome, where it shares its habitat with hundreds of trillions of other microbial cells. Despite weak organic acids (WOAs) being among the most abundant metabolites produced by bacterial microbiota, little is known about their effect on C. albicans. Here we used a sequencing-based profiling strategy to systematically investigate the transcriptional stress response of C. albicans to lactic, acetic, propionic, and butyric acid at several time points after treatment. Our data reveal a complex transcriptional response, with individual WOAs triggering unique gene expression profiles and with important differences between acute and chronic exposure. Despite these dissimilarities, we found significant overlaps between the gene expression changes induced by each WOA, which led us to uncover a core transcriptional response that was largely unrelated to other previously published C. albicans transcriptional stress responses. Genes commonly up-regulated by WOAs were enriched in several iron transporters, which was associated with an overall decrease in intracellular iron concentrations. Moreover, chronic exposure to any WOA lead to down-regulation of RNA synthesis and ribosome biogenesis genes, which resulted in significant reduction of total RNA levels and of ribosomal RNA in particular. In conclusion, this study suggests that gastrointestinal microbiota might directly influence C. albicans physiology via production of WOAs, with possible implications of how this fungus interacts with its host in both health and disease.

MIG1Regulates Resistance of Candida albicans against the Fungistatic Effect of Weak Organic Acids

“…S1B), thus covering a range of acidity levels found throughout the human GI tract (20,27). Overall, these data demonstrate that WOAs possess a specific growth inhibition activity that goes beyond their pH-modulating property, consistent with our previous results on the effects of WOAs on the C. albicans transcriptome (28). Importantly, the inhibition of fungal growth by WOAs was not restricted to C. albicans but was conserved across other yeast species, including the other CTG clade member, Candida parapsilosis, and the non-CTG clade members Candida glabrata and Saccharomyces cerevisiae (Fig.…”

“…While we noticed significant differences in the potency of each molecule, all except lactic acid had specific inhibitory effects at physiologically relevant concentrations and pH values, indicating that WOAs have the potential to inhibit C. albicans growth in various body sites. Furthermore, we recently identified a pH-independent core transcriptional response to all four acids tested (28), suggesting the existence of a common transcriptional regulatory circuit responding to WOAs in C. albicans. According to our genetic screen, only a single TF mutant strain (hms1⌬) displayed a higher resistance to one of the WOAs (i.e., propionic acid), while 21 had significantly increased levels of sensitivity to one or more WOAs (Fig.…”

“…Significant reductions in optical density were observed at both 6 and 24 h after WOA treatment initiation, indicating that these compounds have a long-lasting and not just an acute effect on C. albicans growth (28). Moreover, little or no significant decrease in cell viability was observed with any of the acids tested, indicating a fungistatic rather than a fungicidal effect ( Fig.…”

“…Could these metabolites normally restrict C. albicans growth? With the exception of a few studies (21,22,28,31,39), little was known about the effects of WOAs on C. albicans. Here, we extended these previous studies by systematically and quantitatively analyzing the effects of lactic, acetic, propionic, and butyric acid on fungal growth via robotically assisted high-throughput assays.…”

β-glucan Exposure on the Fungal Cell Wall Tightly Correlates with Competitive Fitness of Candida Species in the Mouse Gastrointestinal Tract

“…Half-maximal effective concentrations (EC 50 ) were determined by non-linear regression in GraphPad Prism. The half-maximal inhibitory concentrations (IC 50 ) of acetic and lactic acid on fungal growth were determined in vitro via turbidimetric assays as described previously (Cottier et al, 2015a) with some minor modifications (refer to Supplemental Methods). Oxidative stress resistance was determined on PBS-washed overnight cultures incubated in PBS at 37°C for 2 h. Cells were then treated with a range of tert -Butyl hydroperoxide ( t BOOH) concentrations, incubated at 37°C for 1 h and subjected to live/dead analysis as described above.…”