The transcriptional stress response of Candida albicans to weak organic acids.
Bottom Line: 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.
Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.Show MeSH
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Mentions: Although only a relatively low overall overlap was found between the published list of genes regulated under low iron and all differentially expressed genes found in this study (Figure 3A), iron homeostasis was among the few consistently enriched GO biological processes found across all time points and all WOAs (Figure 2B), and many of the core transcriptional response genes were previously reported to be modulated in low iron conditions in the same direction as our data revealed in response to WOAs (Table S2) (Lan et al. 2004; Ramanan and Wang 2000). Based on these findings, we hypothesized that C. albicans treated with WOAs might enter a physiological state that, at least in part, resembles the one adopted in a low iron environment. We therefore employed a colorimetric assay (Hsu et al. 2011) to quantitatively measure the concentration of iron in both the culture media and supernatants of cells treated with WOAs as well as in cell pellets from the same cultures. Whereas in no case the amount of iron in the extracellular space was found to be limiting for growth (Figure 4A), we surprisingly observed that, as early as 4 hr after incubation with any of the four WOAs the intracellular concentration of iron was reduced by ~60% compared with the untreated cells (Figure 4B). In contrast, in control cultures treated for the same amount of time with HCl to match the same pH (5.5) or with unrelated compounds also known to affect the growth of C. albicans to the same extent (i.e., nourseothricin or NaCl), the intracellular iron concentration was only reduced by ~21% or ~15%, respectively. These results show for the first time that WOAs are endowed with the specific effect of reducing intracellular iron concentrations in C. albicans. Because WOAs reduced C. albicans growth (Figure 1B) (Huang et al. 2011), and iron is essential for growth of this species (Ramanan and Wang 2000; Lan et al. 2004), we therefore tested whether alteration of intracellular iron concentrations played a role in the inhibition of C. albicans growth by WOAs. To this end we used a mutant strain (sfu1Δ) previously shown to import more iron than wild type (Chen et al. 2011) to test whether counteracting the decreased intracellular iron concentrations would counteract the growth-inhibitory effect of WOAs. As expected, sfu1Δ C. albicans cells displayed a twofold increase in intracellular iron concentration both in presence and in absence of butyric acid, which brought the intracellular iron concentration of WOA-treated sfu1Δ cells to closely resemble the one of untreated wild-type cells (Figure 4C). However, butyric acid had a similar effect on the growth of mutant and wild-type cells, indicating that restoring normal intracellular iron levels is not sufficient to bypass the growth inhibition imposed by WOAs on C. albicans.
Affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.