Epithelial activation by Candida species

J. R. Naglik

Author address: 

King’s College London, LONDON, United Kingdom

Abstract: 

Objective: Candida albicans causes mucosal and life threatening systemic infections that contribute to high morbidity and mortality. C. albicans hyphae damage host tissue by secreting Candidalysin, a peptide toxin that permeabilises epithelial membranes, triggers c-Fos/MKP-1 signalling pathways, and activates epithelial immunity. Analysis of Ece1p amino acid sequences from different Candida species has revealed that additional putative Candidalysin toxins are also present in C. dubliniensis, C. tropicalis and C. maltosa. We compared the different Candidalysins for their ability to cause damage, activate c-Fos/MKP-1 signalling and immune responses in epithelial cells in vitro. Furthermore, we assessed the importance of the C. albicans Candidalysin in mucosal and systemic murine models of infection. Methods: Activation of epithelial signalling pathways was investigated by Western blotting. Immune induction was determined by quantification of secreted cytokines by Luminex. Damage was quantified by lactate dehydrogenase assay. Pathogenicity of Candidalysin-expressing and non-expressing C. albicans strains was assessed in vivo using two mucosal models of oropharyngeal candidiasis and vaginitis, and a systemic intravenous model. Results: In vitro studies demonstrate that the Candidalysins from C. albicans, C. dubliniensis, C. tropicalis and C. maltosa are all capable of damaging epithelial cells, activating c-Fos/MKP-1 signalling pathways, and inducing pro-inflammatory cytokine responses, despite differences in amino acid sequence. In vivo, only Candidalysin-expressing C. albicans strains were able to damage the host or induce pro-inflammatory cytokines and recruitment of neutrophils to the site of infection. Non-expressing C. albicans strains were all attenuated in virulence. Conclusion: We identify the Candidalysins as a conserved family of fungal peptide toxins, provide mechanistic insights into Candidalysin function, and demonstrate a critical role for Candidalysin in mucosal and systemic C. albicans infections.

2018

abstract No: 

S7.2a

Full conference title: 

20th Congress of the International Society for Human and Animal Mycology, Amsterdam, the Netherlands
    • ISHAM 20th (2018)