Exploring the role of Candida albicans Ece1 peptides in promoting fungal gut commensalis

Candida albicans, an opportunistic fungal pathogen, poses a significant risk to human health by causing very frequently superficial infections, but also severe systemic infections under certain predisposing conditions. The current dogma of C. albicans commensalism is that the yeast morphology is the preferred growth form during gut colonization, while hyphae are detrimental for commensal growth in the gut and rather required and indispensable for pathogenesis. Hypha formation is associated with a strong induction of the gene ECE1, encoding candidalysin (CaL) - the first (ribosomal) peptide toxin identified in a human pathogenic fungus – and seven additional non-candidalysin Ece1 peptides (NCEPs). While CaL directly inflicts damage to human cells, we propose that Ece1 may also act on bacteria of the human microbiota during commensalism.

Using in vivo competition models, we confirmed that the yeast morphology in fact favors murine gut colonization in models using antibiotics to remove antagonistic bacteria. However, hypha formation plays a crucial role to facilitate C. albicans colonization in hosts with either an undisturbed gut microbiota or carrying specific bacterial populations. In these niches, hyphal competent C. albicans wildtype cells exhibited a fitness advantage over yeast-locked mutant cells, promoting successful colonization. This attribute is primarily due to the expression of ECE1.

We explored the effects of Ece1 on co-colonizing bacteria by assessing the susceptibility of selected bacteria from different body sites to Ece1 peptides. Our screening revealed that CaL influences the growth of several members of the microbiota and modulates bacterial properties. We are currently analyzing the transcriptional response of gut bacteria to CaL stimulation to understand the mechanisms of Candida-bacteria cross-kingdom interactions.

Our study provides evidence that CaL has evolved to improve fungal fitness during competition with bacterial members of the human microbiota, shaping microbial communities during commensalism or polymicrobial infections in the human gut through inter-kingdom competition.