Fungal determinants contributing to translocation of <i>Candida albicans</i> yeast cells through the intestinal epithelial barrier

Filamentous hyphae are the main invasive morphotype of the opportunistic fungal pathogen <i>Candida albicans</i>. However, yeast cells seem better suited for dissemination through the bloodstream during the progression of life-threatening systemic infections. While yeast cells are present together with hyphae in the intestine during commensal colonization, how yeast cells ultimately reach the blood following translocation of invasive hyphae is unknown. In this study we investigated potential mechanisms proposed for how yeast cells may enter the blood using an <i>in vitro</i> model of translocation based on intestinal epithelial cells (IECs). Our data show that yeast cells can passively translocate with invasive hyphae, though this requires host-cell damage facilitated by the peptide toxin candidalysin, encoded by <i>ECE1</i>. Independent of fungal-mediated damage, chemical disruption of the IEC layer by the mycotoxin patulin was sufficient to foster efficient translocation of <i>C. albicans</i> yeast cells alone. This was dependent on a significant loss of barrier integrity rather than host-cell damage itself. The same phenomenon was observed for oral clinical isolates, which more readily grow as yeast and pseudohyphal cells as compared to the standard SC5314 strain. The transition of hypha-to-yeast growth was also associated with translocation across IECs by increased expression of the yeast-essential gene <i>PES1</i>. This is the first study to directly investigate the mechanisms by which <i>C. albicans</i> yeast cells can translocate across IECs and to describe the fungal factors that contribute to this process.