Control of mucosal candidiasis in the zebrafish swimbladder depends on neutrophils that block filament invasion and drive extracellular trap production

Candida albicans is a ubiquitous mucosal commensal that is normally prevented from causing acute or chronic invasive disease. Neutrophils contribute to protection in oral infection but exacerbate vulvovaginal candidiasis. To dissect the role of neutrophils during mucosal candidiasis we took advantage of a new, transparent zebrafish swimbladder infection model. Intravital microscopic tracking of individual animals revealed that blocking neutrophil recruitment leads to rapid mortality in this model through faster disease progression. Conversely, artificial recruitment of neutrophils during early infection reduces disease pressure. Non-invasive longitudinal tracking showed that mortality is a consequence of C. albicans breaching the epithelial barrier and invading surrounding tissues. Accordingly, we found that a hyperfilamentous C. albicans strain breaches the epithelial barrier more frequently and causes mortality in immunocompetent zebrafish. Lack of neutrophils at the infection site is associated with less fungal-associated extracellular DNA and less damage to fungal filaments, suggesting that neutrophil extracellular traps help to protect the epithelial barrier from C. albicans breach. We propose a homeostatic model where C. albicans disease pressure is balanced by neutrophil-mediated damage of fungi, maintaining this organism as a commensal while minimizing risk of damage to host tissue. The unequalled ability to dissect infection dynamics at high spatio-temporal resolution makes this zebrafish model a unique tool for understanding mucosal host-pathogen interactions.