# The fungal peptide toxin candidalysin induces distinct membrane repair mechanisms compared to bacterial pore-forming toxins

## TL;DR

This study compares how cells repair membrane damage caused by the fungal toxin candidalysin versus bacterial toxins, revealing unique protective mechanisms.

## Contribution

The study identifies distinct Ca2+-dependent repair mechanisms specific to candidalysin compared to bacterial pore-forming toxins.

## Key findings

- Candidalysin triggers Ca2+-dependent repair but lacks significant protection from patch repair or ceramide.
- MEK-dependent repair and annexins A1, A2, and A6 partially repair candidalysin-induced damage.
- Extracellular Cl- improves cell survival after candidalysin challenge, but not after SLO or aerolysin.

## Abstract

The common fungal pathogen, Candida albicans, relies on the pore-forming toxin candidalysin to damage host cells. Cells counteract pore-forming toxins by Ca2+-dependent mechanisms, such as microvesicle shedding and annexin recruitment to resist cholesterol-dependent cytolysins like streptolysin O (SLO), or annexin involvement and patch repair in the case of aerolysin. However, the specific Ca2+-dependent repair pathways engaged in response to candidalysin remain poorly understood. Here, we determined the involvement of different Ca2+-dependent repair mechanisms to candidalysin and compared responses to SLO and aerolysin using flow cytometry and high-resolution microscopy. We report that candidalysin triggered Ca2+-dependent repair, but patch repair and ceramide failed to provide significant protection. MEK-dependent repair and annexins A1, A2 and A6 contributed partially to repairing damage caused by candidalysin. However, annexin translocation after candidalysin challenge was delayed compared to SLO or aerolysin challenge. Surprisingly, extracellular Cl- improved cell survival after candidalysin challenge, but not after challenge with SLO or aerolysin. Finally, we found that candidalysin is removed via extracellular vesicle shedding. These findings reveal that Ca2+-dependent microvesicle shedding protects cells from candidalysin and can be engaged by multiple molecular mechanisms during membrane repair.