A protein fragment released by filaments of the fungus Candida albicans destroys host cells. This is the first demonstration that human fungal pathogens other than moulds can release toxic peptides.
Subject terms:
The fungus Candida albicans, a common cause of infection in mucosal tissues, forms long filaments called hyphae, comprised of tubular cells, that are required for virulence in animals. Hyphal-associated adhesion proteins bind to host tissue, which is then degraded by hydrolytic enzymes. However, until now, no hyphal toxin that damages host cells has been identified. Because of this, the fungus is considered to be an 'accidental' pathogen that benignly inhabits our mucosal tissues, causing tissue damage by happenstance rather than design. That view must now change drastically. Moyes et al. reveal a mechanism through which hyphae actively wage war on our cells — the production of a toxin that the authors call Candidalysin.
Interactions between C. albicans and epithelial cells, which line the body's cavities, occur during the early stages of mucosal infections such as thrush and vaginitis. Hyphae elicit several epithelial-cell responses, including the production of signalling molecules called cytokines that recruit cells of the immune system to defend tissues, and loss of cell integrity through cell-membrane deterioration. Moyes et al. discovered that a strain of C. albicans in which the geneECE1 was mutated could not elicit epithelial-cell responses, despite growing apparently normal hyphae. Moreover, the authors validated these tissue-culture observations in vivo — the ECE1mutant was unable to reliably infect mucosa in a zebrafish swimbladder model and a mouse model of thrush.
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. In fact, 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. Thus, the function of the Ece1 protein has remained a puzzle.
How does Ece1 promote epithelial-cell responses? The protein's amino-acid sequence suggests that it is secreted from hyphae as a group of eight short protein fragments, or peptides, and so would be well positioned to interact with host cells. Moyes and colleagues confirmed that all eight Ece1 peptides are secreted from hyphae. Analysis of synthetic versions of each peptide revealed that one, Ece1-III, elicits the same responses from epithelial cells as do hyphae. Moreover, precise deletion of the genetic region that codes for only Ece1-III created a mutant C. albicansthat secreted the remaining seven peptides, but did not elicit epithelial-cell responses or cause mucosal disease in animal models. These results clearly demonstrate that Ece1-III mediates the pathogenic activity associated with ECE1.
By what mechanism does Ece1-III exert this activity? Certain chemical and structural features indicate that Ece1-III might function like peptide toxins, such as the bee-venom toxin melittin. Indeed, the authors show that the peptide causes rapid and transient permeabilization of artificial cell membranes in vitro. These activities are enhanced in the presence of cholesterol, a component of animal — but not fungal — membranes. The researchers conclude that Ece1-III acts as a peptide toxin, which they name Candidalysin.
Moyes and colleagues' study establishes that C. albicans hyphae evolved to damage host cells. When combined with our knowledge of hyphal adhesin proteins and enzymes, a simple program of tissue destruction emerges (Fig. 1). First, the hyphal-specific adhesin Hwp1 attaches to mucosal surfaces. Second, the hyphal-specific invasion protein Als3, acting with the protein Ssa1, binds to receptors on the surface of the host cell, promoting engulfment of the hypha by the host cell8. Finally, Candidalysin accumulates in the invasion pocket around the hypha, attacking the host's cholesterol-containing membrane.
The pathogenic fungus Candida albicans infects its host by forming filamentous structures called hyphae. Proteins on the hyphal surface — the adhesin Hwp1, the invasin Als3 and its partner Ssa1 — make contact with the host cell directly or through receptor proteins to promote adhesion and engulfment of the hypha by the host. Moyes et al.2 report that the protein Ece1 is secreted from the hypha as eight short peptides. One of these, Candidalysin, acts as a toxin that accumulates in the invasion pocket and attacks the host-cell membrane, leading to membrane permeabilization and the induction of host defences.
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. However, impaired defences in people with conditions such as AIDS, diabetes and some cancers permit C. albicans growth and consequent disease.
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