<EM>CANDIDA ALBICANS</EM>-INDUCED ITCH: HYPHAL-DERIVED MEDIATORS DIRECTLY ACTIVATE CAPSAICIN-SENSITIVE NERVE FIBERS

The sensation of itch is a hallmark of Candida albicans infections, yet the fungal drivers of this response remain poorly defined. This study investigated whether mediators specifically associated with the pathological, hyphal form of C. albicans—namely biofilm-derived extracellular vesicles (bdEVs) and Candidalysin (CL), the first identified fungal peptide toxin—function as direct signaling drivers of pruriceptive pathways. Using an ex vivo innervated mouse skin preparation, we demonstrate that bdEVs activate a majority of cutaneous C-fibers (67%), inducing 26±6 action potentials, n=4. This effect was mimicked by CL, which activated 50% of C-fibers in a dose-dependent manner, with a maximally effective concentration (30µM) eliciting 20±3 action potentials (n=6). Calcium imaging of dissociated dorsal root ganglion (DRG) neurons revelead that CL-induced activation is direct, targeting a specific subpopulation of neurons (19/65) of which 95% were responsive to TRPV1 agonist, capsaicin. To determine the behavioral relevance of this activation, we utilized a mouse cheek injection model to differentiate between pruriceptive (scratching) and nociceptive (wiping) responses. Intradermal injection of both bdEVs (10^12 particles/10µl) and CL (100 µg/10µl) significantly increased scratching bouts compared to controls (bdEVs:42±3 vs 22±3, n=9; CL:58±5 vs 20±3, n=10), while no significant difference was observed in wiping behavior. These findings demonstrate that C. albicans biofilm-derived EVs and Candidalysin directly activate capsaicin-sensitive sensory fibers and selectively induce itch, providing a direct pathological link between hypha-associated products and sensory nerve activation.
Funded by the EU NextGenerationEU through the Recovery and Resilience Plan for Slovakia (No. 09I03-03-V04-00206).