Damage to the host

The mechanism by which Candida albicans damages host cells has been considered to be multi-factorial, and presumed to rely on a combination of adhesion, invasion, hyphal extension, turgor pressure and the secretion of hydrolytic enzymes. Although toxin production by C. albicans has long been postulated and the culture supernatants of C. albicans hyphae have been shown to exhibit haemolytic activity, the mechanism underlying C. albicans’ ability to lyse host cells has remained elusive. It is clear that hyphae are crucial for adhesion, invasion and damage. Thus, host cell damage is caused by hyphae and/or a hyphal associated factor. However, the exact molecular mechanisms by which C. albicans destroys these host cells has remained enigmatic.

We have identified a peptide toxin, secreted by C. albicans, which has remarkable similarities with melittin – the major component of bee venom. By deleting the encoding gene and in vitro synthesis of the fragment, we have shown that this peptide is, in itself, essential and sufficient for the lysis of host cells. In collaboration with Dr Julian Naglik, Kings College London/UK and other cooperation partners, we elucidated intracellular processing of the Ece1 polyprotein into different peptides including the secreted, damage-mediating candidalysin. Ongoing work and cooperations, e.g. with Dr Thomas Gutsmann, Forschungszentrum Borstel/Germany, now examine the exact mechanism by which this potent C. albicans cytolysin disrupts host cell integrity and investigate the role of non-candidalysin Ece1 peptides (NCEPs, PI-II, IV-VIII) for the biology of C. albicans and its interaction with the host.

Staff

Stefanie Allert
Annika König
Selene Mogavero
Rita Müller

Publications

Richardson JP, Brown R, Kichik N, Lee S, Priest E, Mogavero S, Maufrais C, Wickramasinghe DN, Tsavou A, Kotowicz NK, Hepworth OW, Gallego-Cortés A, Ponde NO, Ho J, Moyes DL, Wilson D, D'Enfert C, Hube B, Naglik JR (2022) Candidalysins are a new family of cytolytic fungal peptide toxins. mBio 13(1), e0351021.
Westman J, Plumb J, Licht A, Yang M, Allert S, Naglik JR, Hube B, Grinstein S, Maxson ME (2022) Calcium-dependent ESCRT recruitment and lysosome exocytosis maintain epithelial integrity during Candida albicans invasion. Cell Rep 38(1), 110187.
Austermeier S, Pekmezović M, Porschitz P, Lee S, Kichik N, Moyes DL, Ho J, Kotowicz NK, Naglik JR, Hube B, Gresnigt MS (2021) Albumin neutralizes hydrophobic toxins and modulates Candida albicans pathogenicity. mBio 12(3), e0053121.
d'Enfert C, Kaune AK, Alaban LR, Chakraborty S, Cole N, Delavy M, Kosmala D, Marsaux B, Fróis-Martins R, Morelli M, Rosati D, Valentine M, Xie Z, Emritloll Y, Warn PA, Bequet F, Bougnoux ME, Bornes S, Gresnigt MS, Hube B, Jacobsen ID, Legrand M, Leibundgut-Landmann S, Manichanh C, Munro CA, Netea MG, Queiroz K, Roget K, Thomas V, Thoral C, Van den Abbeele P, Walker AW, Brown AJP (2021) The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives. FEMS Microbiol Rev 45(3), fuaa060. (Review)
Last A, Maurer M, Mosig AS, Gresnigt MS, Hube B (2021) In vitro infection models to study fungal-host interactions. FEMS Microbiol Rev 45(5), fuab005. (Review)
Liu J, Willems HME, Sansevere EA, Allert S, Barker KS, Lowes DJ, Dixson AC, Xu Z, Miao J, DeJarnette C, Tournu H, Palmer GE, Richardson JP, Barrera FN, Hube B, Naglik JR, Peters BM (2021) A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis. PLoS Pathog 17(9), e1009884.
Mogavero S, Sauer FM, Brunke S, Allert S, Schulz D, Wisgott S, Jablonowski N, Elshafee O, Krüger T, Kniemeyer O, Brakhage AA, Naglik JR, Dolk E, Hube B (2021) Candidalysin delivery to the invasion pocket is critical for host epithelial damage induced by Candida albicans. Cell Microbiol 23(10), e13378.
Pekmezovic M, Hovhannisyan H, Gresnigt MS, Iracane E, Oliveira-Pacheco J, Siscar-Lewin S, Seemann E, Qualmann B, Kalkreuter T, Müller S, Kamradt T, Mogavero S, Brunke S, Butler G, Gabaldón T, Hube B (2021) Candida pathogens induce protective mitochondria-associated type I interferon signalling and a damage-driven response in vaginal epithelial cells. Nat Microbiol 6(5), 643-657.
Pekmezovic M, Kalagasidis Krusic M, Malagurski I, Milovanovic J, Stępień K, Guzik M, Charifou R, Babu R, O'Connor K, Nikodinovic-Runic J (2021) Polyhydroxyalkanoate/Antifungal polyene formulations with monomeric hydroxyalkanoic acids for improved antifungal efficiency. Antibiotics (Basel) 10(6), 737.
Pekmezovic M, Kaune AK, Austermeier S, Hitzler SUJ, Mogavero S, Hovhannisyan H, Gabaldón T, Gresnigt MS, Hube B (2021) Human albumin enhances the pathogenic potential of Candida glabrata on vaginal epithelial cells. PLoS Pathog 17(10), e1010037.

Funding