Candidalysins Are a New Family of Cytolytic Fungal Peptide Toxins

Richardson, Jonathan P.; Brown, Rhys; Kichik, Nessim; Lee, Sejeong; Priest, Emily; Mogavero, Selene; Maufrais, Corinne; Wickramasinghe, Don N.; Tsavou, Antzela; Kotowicz, Natalia; Hepworth, Olivia; Gallego-Cortés, Ana; Ponde, Nicole O.; Ho, Jemima; Moyes, David L.; Wilson, Duncan; d’Enfert, Christophe; Hube, Bernhard; Naglik, Julian R.

doi:10.1128/mbio.03510-21

Cited by 26 publications

(30 citation statements)

References 43 publications

(79 reference statements)

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“…This peptide is also called Ece1-III because it is produced as a third of the eight cleaved fragments of cell elongation 1 (Ece1) protein that is specifically expressed in the hypha [2]. The candidate peptide is supposedly amphipathic and consists of 31 amino acids containing hydrophobic amino acid assemblies on two α-helical structures [2,3]. To date, the bioactivity of candidalysin has been investigated from a variety of aspects, especially using an Ece1-deficient strain of C. albicans and the synthetic peptide.…”

Section: Introductionmentioning

confidence: 99%

Solubility affects IL-1β-producing activity of the synthetic candidalysin peptide

et al. 2022

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Candidalysin, a peptide toxin produced specifically from hyphae of Candida albicans, plays a crucial role in C. albicans pathogenesis in the oral cavity and vagina. Synthetic peptides have been widely used in previous studies to investigate the bioactivity of candidalysin. Although the solubility of the peptide, which is expected to have a hydrophobic property, has not been well characterized, candidalysin solutions are usually prepared in water. In this study, we prepared the synthetic peptide candidalysin in water (CLw) or in dimethyl sulfoxide (CLd) and compared their cytotoxicity and interleukin (IL)-1β-producing activity to determine whether the activity of the peptide would be affected. In addition, we evaluated whether the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome pathway or other pathways were involved in their activities. Unexpectedly, we found that CLw was not completely solubilized and contained abundant insoluble microparticles. CLw was active at comparably high concentrations (≥ 10 μM). In contrast, CLd is completely solubilized and sufficiently active at low concentrations, that is, 1 μM or less. CLw showed weak cytotoxicity and NLRP3-dependent and cathepsin B-dependent IL-1β-producing activity, whereas CLd showed strong cytotoxicity and cathepsin B-dependent IL-1β-producing activity. Fractionation of CLw revealed that NLRP3-dependent activity was caused by insoluble microparticles. Furthermore, nanoparticle tracking of CLd revealed that the peptide was present as nanoparticles with a size of 96 nm. CLw contained a small amount of such nanoparticles. Thus, the bioactivities of the synthetic peptide candidalysin, especially the IL-1β-producing activity, are affected by the solubility of the peptide depending on the solvent employed. The NLRP3-dependent activity of the synthetic peptide is caused by insoluble microparticles and may not be the intrinsic activity of candidalysin.

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Section: Introductionmentioning

confidence: 99%

Solubility affects IL-1β-producing activity of the synthetic candidalysin peptide

et al. 2022

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“…Since candidalysin is a classic virulence factor that involves a strong host immune response, species that prefer a more commensal mode of existence are unlikely to exploit its potential to that extent [93]. In the case of C. auris, the ECE1 gene has not been detected in the genome and, according to current knowledge, this species does not produce candidalysin [92].…”

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confidence: 98%

“…Orthologs of candidalysin from C. albicans have also been found in C. dubliniensis and C. tropicalis [92]. Interestingly, studies on oral epithelial cells and artificial lipid membranes presented by Richardson et al [92] indicated that candidalysins produced by C. dubliniensis and C. tropicalis have stronger and faster cytolytic and immunostimulatory effects than candidalysin of C. albicans. Importantly, both species cause less damage to epithelial cells than C. albicans, which may be due to lower Ece1 production, processing, or secretion during contact with the host.…”

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confidence: 99%

“…Candidalysin is an amphipathic, α-helical peptide, derived from a polypeptide (Ece1) encoded by the ECE1 gene [90]. Recent studies indicate that candidalysin is one of the key molecules involved in the destabilization of the epithelial plasma membrane and the induction of necrotic cell death [91,92]. Orthologs of candidalysin from C. albicans have also been found in C. dubliniensis and C. tropicalis [92].…”

mentioning

confidence: 99%

“…Recent studies indicate that candidalysin is one of the key molecules involved in the destabilization of the epithelial plasma membrane and the induction of necrotic cell death [91,92]. Orthologs of candidalysin from C. albicans have also been found in C. dubliniensis and C. tropicalis [92]. Interestingly, studies on oral epithelial cells and artificial lipid membranes presented by Richardson et al [92] indicated that candidalysins produced by C. dubliniensis and C. tropicalis have stronger and faster cytolytic and immunostimulatory effects than candidalysin of C. albicans.…”

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confidence: 99%

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Similarities and Differences among Species Closely Related to Candida albicans: C. tropicalis, C. dubliniensis, and C. auris

Satała

Juszczak

Wronowska

et al. 2022

Cellular Microbiology

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Although Candida species are widespread commensals of the microflora of healthy individuals, they are also among the most important human fungal pathogens that under certain conditions can cause diseases (candidiases) of varying severity ranging from mild superficial infections of the mucous membranes to life-threatening systemic infections. So far, the vast majority of research aimed at understanding the molecular basis of pathogenesis has been focused on the most common species—Candida albicans. Meanwhile, other closely related species belonging to the CTG clade, namely, Candida tropicalis and Candida dubliniensis, are becoming more important in clinical practice, as well as a relatively newly identified species, Candida auris. Despite the close relationship of these microorganisms, it seems that in the course of evolution, they have developed distinct biochemical, metabolic, and physiological adaptations, which they use to fit to commensal niches and achieve full virulence. Therefore, in this review, we describe the current knowledge on C. tropicalis, C. dubliniensis, and C. auris virulence factors, the formation of a mixed species biofilm and mutual communication, the environmental stress response and related changes in fungal cell metabolism, and the effect of pathogens on host defense response and susceptibility to antifungal agents used, highlighting differences with respect to C. albicans. Special attention is paid to common diagnostic problems resulting from similarities between these species and the emergence of drug resistance mechanisms. Understanding the different strategies to achieve virulence, used by important opportunistic pathogens of the genus Candida, is essential for proper diagnosis and treatment.

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β-Nitrostyrene derivatives as broad range potential antifungal agents targeting fungal cell wall

Ramzan

Padder²,

Masoodi³

et al. 2022

European Journal of Medicinal Chemistry

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Candidalysins Are a New Family of Cytolytic Fungal Peptide Toxins

Abstract: Pathogenic fungi kill an estimated 1.5 million people every year. Recently, we discovered that the fungal pathogen Candida albicans secretes a peptide toxin called candidalysin during mucosal infection.

Cited by 26 publications

References 43 publications

Solubility affects IL-1β-producing activity of the synthetic candidalysin peptide

Solubility affects IL-1β-producing activity of the synthetic candidalysin peptide

Similarities and Differences among Species Closely Related to Candida albicans: C. tropicalis, C. dubliniensis, and C. auris

β-Nitrostyrene derivatives as broad range potential antifungal agents targeting fungal cell wall

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