<i>Candida albicans</i> promotes TSST-1 production by <i>Staphylococcus aureus</i> through glucose depletion and relief of CcpA-mediated repression

Menstrual toxic shock syndrome (mTSS) is a rare yet life-threatening disease that is caused when the opportunistic pathogenic bacterium <i>Staphylococcus aureus</i> releases the toxic shock syndrome toxin 1 (TSST-1) superantigen, which triggers systemic inflammation. The main risk factor for mTSS is prolonged use of intravaginal products, which facilitates <i>S. aureus</i> growth and TSST-1 production in menstrual blood. However, some studies suggest that the vaginal microbiota may also play a role in mTSS occurrence. A previous study reported that the presence of <i>S. aureus</i> in menstrual fluids was correlated with the simultaneous presence of <i>Candida</i> species, particularly <i>C. albicans</i>. Here, we assessed the potential involvement of <i>C. albicans</i> in the stimulation of TSST-1 production by incubating <i>S. aureus</i> strains with <i>C. albicans</i> culture supernatants and measuring TSST-1 production. We found that the growth of <i>C. albicans</i> depleted the available glucose, thereby alleviating the CcpA-mediated repression of the <i>tst</i> gene, which encodes TSST-1, and enabling activation of its expression by SaeRS activity. These results highlight the importance of vaginal microbiota and nutrient availability with regard to the regulation of <i>S. aureus</i> virulence in the context of mTSS.IMPORTANCEMenstrual toxic shock syndrome (mTSS) is a life-threatening disease caused by toxic shock syndrome toxin 1 (TSST-1)-producing strains of <i>Staphylococcus aureus</i>. While tampons are a known risk factor, the vaginal microbiota may also increase mTSS risk. Our findings reveal that the yeast <i>Candida albicans</i>, a frequent colonizer of the vaginal mucosa, stimulates TSST-1 production of <i>S. aureus</i> by depleting glucose, a key regulator of <i>tst</i> gene expression. This study highlights how <i>C. albicans</i>, which is part of the vaginal microbiota, can amplify <i>S. aureus</i> virulence through metabolic interactions. These findings may also carry clinical implications by identifying vaginal colonization with <i>C. albicans</i> as a potential biomarker for heightened mTSS susceptibility, specifically in individuals harboring TSST-1-producing strains of <i>S. aureus</i>.