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

Abstract

bCandida albicans is the leading cause of fungal infections; but it is also a member of the human microbiome, an ecosystem of thousands of microbial species potentially influencing the outcome of host-fungal interactions. Accordingly, antibacterial therapy raises the risk of candidiasis, yet the underlying mechanism is currently not fully understood. We hypothesize the existence of bacterial metabolites that normally control C. albicans growth and of fungal resistance mechanisms against these metabolites. Among the most abundant microbiota-derived metabolites found on human mucosal surfaces are weak organic acids (WOAs), such as acetic, propionic, butyric, and lactic acid. Here, we used quantitative growth assays to investigate the dose-dependent fungistatic properties of WOAs on C. albicans growth and found inhibition of growth to occur at physiologically relevant concentrations and pH values. This effect was conserved across distantly related fungal species both inside and outside the CTG clade. We next screened a library of transcription factor mutants and identified several genes required for the resistance of C. albicans to one or more WOAs. A single gene, MIG1, previously known for its role in glucose repression, conferred resistance against all four acids tested. Consistent with glucose being an upstream activator of Mig1p, the presence of this carbon source was required for WOA resistance in wild-type C. albicans. Conversely, a MIG1-complemented strain completely restored the glucose-dependent resistance against WOAs. We conclude that Mig1p plays a central role in orchestrating a transcriptional program to fight against the fungistatic effect of this class of highly abundant metabolites produced by the gastrointestinal tract microbiota.O ver 60% of fungal infections are caused by Candida albicans, and these infections range from debilitating skin or mucosal infections to potentially lethal disseminated disease, most especially in immunocompromised individuals and in nosocomial settings (1, 2). At the same time, this species is also the fungus most frequently isolated from the oral cavity, the vaginal mucosa, and the gastrointestinal (GI) tract of most healthy individuals (2), indicating a commensal nature of the host-microbe interaction in unperturbed conditions. A switch from asymptomatic colonization to opportunistic infection is supported by evidence of strain relatedness between C. albicans isolates from blood cultures and from the GI tract of the same patients (3). Hence, controlling C. albicans growth in the GI tract might limit one of the primary sources of systemic candidiasis.Antibiotic treatment, which is well known to profoundly modify the GI microbiome (4, 5), is a strong risk factor for both vulvovaginal and systemic candidiasis in humans (6, 7). Moreover, most mouse models of C. albicans GI colonization rely on oral antibiotic treatment (8-10). Other models rely on the use of germfree mice (11), infant mice (12, 13), which harbor a significantly different GI microbiome than adults (14), or ...

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

“…Secretion of the mouse cathelicidin-related antimicrobial peptide (mCRAMP) in the GI lumen was recently shown to play an important role in controlling C. albicans colonization in the mouse GI tract (Fan et al, 2015); however no significant correlation between mouse GI tract fitness and mCRAMP resistance was observed (Figure 4B). Microbiota-derived weak organic acids, such as acetic and lactic acid, were shown to be fungistatic and proposed to contribute to colonization resistance against C. albicans in the mouse GI tract (Cottier et al, 2015b), however Candida strains and species displaying the highest competitive fitness in the mouse GI tract did not show a significant increase in acetic acid or lactic acid resistance (Figures 4C,D). An important feature of gut commensal microbes is their ability to survive in the presence of bile (Strati et al, 2016), but GI fitness was uncorrelated to resistance to ox bile or bile salts (Figures 4E,F).…”

The role of Lactobacillus species in the control of Candida via biotrophic interactions

“…The involved pathways differ between species. For example, CaMig1, a transcription factor associated with glucose repression, was discovered as a central regulator of weak organic acid like lactic, acetic, propionic, and butyric acid resistance in C. albicans, however, it is only active in the presence of glucose [112]. In fact, glucose is limited in the vaginal tract [113], making this glucose-dependent response unlikely to contribute to lactic acid resistance in the vaginal environment.…”

The CgHaa1-Regulon Mediates Response and Tolerance to Acetic Acid Stress in the Human Pathogen Candida glabrata

“…In C. albicans , response and tolerance to acetic acid was found to be largely dependent on the transcription factor Mnl1, which controlled a substantial percentage of the genes activated by the acid (Ramsdale et al 2008). More recently, it was also shown that the glucose-regulated transcription factor Mig1 plays an important role in providing protection against the toxic effect exerted by acetic acid and other organic acids in acidic environments (Cottier et al 2015b). No significant homolog of ScHaa1 was found in C. albicans , but in C. glabrata the ORF CAGL0L09339g encodes a protein with similarity to ScHaa1, particularly in the N-terminal region.…”