Yeast Infections: from Commensal to Pathogen

-From 2016, articles commented in the Journal and Focus will be posted here (selection by Prof. JH Saurat M.D.)

Yeast Infections: from Commensal to Pathogen

Postby CFH » Tue Apr 12, 2016 8:16 am

Candidalysin is a fungal peptide toxin critical for mucosal infection.
Moyes DL, Wilson D, Richardson JP, Mogavero S, Tang SX, Wernecke J, Höfs S, Gratacap RL, Robbins J, Runglall M, Murciano C, Blagojevic M, Thavaraj S, Förster TM, Hebecker B, Kasper L, Vizcay G, Iancu SI, Kichik N, Häder A, Kurzai O, Luo T, Krüger T, Kniemeyer O, Cota E, Bader O, Wheeler RT, Gutsmann T, Hube B, Naglik JR.
Nature. 2016 Mar 30. doi: 10.1038/nature17625.

What do we learn from this study ?
Candida yeast normally life peacefully within hosts…they are then known as commensals.
-Following gene activation, Candidalysin is secreted and initiates aggression (infection) of host cells…this results clinically in Candidiasis (and Thrush)

-Candida yeast infections presents as small creamy pustules on an erythematous base mostly on mucosal surfaces (oral, genital). It is also referred as thrush the the orapharyngeal mucosal surfaces are affected.
-The cause of candiadiasis is a yeast (Candida Albicans) but no toxin was ever identified before this study and an effective treatment already exists.

-In this study from Germany published in Nature the authors revealed a toxin secreted by candida organisms and coded by the ECE1 gene (more precisely ECE1-III as ECE codes 8 peptides)). This secreted toxin (called candidalysin) directly damages epithelial membranes, triggers a danger response signaling pathway and activates epithelial immunity:

A-epithelial membranes are degraded in the presence of cholesterol which is a normal component in animals, but not in fungal membranes.
Full mechanism:

-First, an adhesion molecule (Hwp1) attaches to mucosal surfaces.
-Second,the protein complex Als3 +,Ssa1, binds to receptors on the surface of the host cell, promoting engulfment of the hypha by the host cell.
-Finally, Candidalysin accumulates in the invasion pocket around the hypha, attacking the he host’s cholesterol-containing membrane

B-host immune responses are activated to keep the Candida population in check…this is impaired in people with AIDS, diabetes mellitus and certain cancers

In one sentence: this attack leads to membrane permeabilization, leakage of cell contents and a defensive cytokine response, which serves to limit the size of the C. albicans population in healthy individuals.


-It is interesting to note that when the ECE1 gene is mutated, the mucosa remains normal and the candida hyphae (thread-like structures of the yeast) grow normally SEPARATELY (In vivo candida cultures, the yeast is unable to infect mucosa in a zebrafish swimbladder as well as in a mouse model of thrush. This means that an inactive ECE1 gene results in a Candida species behaving as a commensal, not a pathogen.

About the ECE1 gene
-ECE1 was one of the first genes to be identified in hyphal-specific expression screens more than 20 years ago, yet until now it has been one of the most poorly understood genes in C. albicans.
-ECE1 is among the most highly expressed genes in hyphae, but its role has not previously been investigated thoroughly because mutants show no defects in hyphal morphology or cell proliferation
-The ECE1 gene codes for 8 short protein fragments and ECE1-III is responsible for the pathogenetic activity of ECE1 by coding for a peptide called ECE1-III

[b]Take Home Message
-The ECE1 gene and its peptides regulate Candida interactions with the host and its activity determines whether candida behaves as a commensal or a pathogen.
-The ECE1 gene and Ece1 peptides (particularly) candidalysin are potential targets of future antifungal drugs.

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