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.

Structure of the Ece1 protein. Ece1 peptides (PI–VIII) are separated by lysine-arginine residues (KR) at their C-termini, which serve as recognition sites of the Kex2 protease. SP, signal peptide.

<em>C. albicans</em> hyphae invade epithelial cells forming invasion pockets. Secreted candidalysin forms pores in the surrounding host membrane causing host cell damage, detected by released cytoplasmic content including lactate dehydrogenase (LDH). — *C. albicans* hyphae invade epithelial cells forming invasion pockets. Secreted candidalysin forms pores in the surrounding host membrane causing host cell damage, detected by released cytoplasmic content including lactate dehydrogenase (LDH).

Publications

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 , e0053121. Details PubMed

Last A, Maurer M, Mosig AS, Gresnigt MS, Hube B (2021) In vitro infection models to study fungal-host interactions. FEMS Microbiol Rev [Epub ahead of print] Details PubMed Open Access PDF

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. Details PubMed Data

Sprenger M, Brunke S, Hube B, Kasper L (2021) A TRP1-marker-based system for gene complementation, overexpression, reporter gene expression, and gene modification in Candida glabrata. FEMS Yeast Res 20(8), foaa066. Details PubMed Open Access PDF

Zhang S, Edwards TN, Mogavero S, Hube B, Berman J, Bougnoux ME, D'Enfert C, Kaplan DH (2021) ATP released by Candida albicans is associated with reduced skin infectivity. J Invest Dermatol S0022-202X(21), 01117-9. Details PubMed

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 (2020) The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives. FEMS Microbiol Rev , fuaa060. (Review) Details PubMed Open Access PDF

Ho J, Wickramasinghe DN, Nikou SA, Hube B, Richardson JP, Naglik JR (2020) Candidalysin is a potent trigger of alarmin and antimicrobial peptide release in epithelial cells. Cells 9(3), 699. Details PubMed Open Access PDF

Kämmer P, McNamara S*, Wolf T, Conrad T, Allert S, Gerwien F, Hünniger K, Kurzai O, Guthke R, Hube B, Linde J, Brunke S (2020) Survival strategies of pathogenic Candida species in human blood show independent and specific adaptations. mBio 11(5), e02435-20. Details PubMed Open Access PDF

König A, Müller R, Mogavero S, Hube B (2020) Fungal factors involved in host immune evasion, modulation and exploitation during infection. Cell Microbiol 23(1), e13272. (Review) Details PubMed Open Access PDF

Ruben S, Garbe E, Mogavero S, Albrecht-Eckardt D, Hellwig D, Häder A, Krüger T, Gerth K, Jacobsen ID, Elshafee O, Brunke S, Hünniger K, Kniemeyer O, Brakhage AA, Morschhäuser J, Hube B, Vylkova S, Kurzai O, Martin R (2020) Ahr1 and Tup1 contribute to the transcriptional control of virulence-associated genes in Candida albicans. mBio 11(2), e00206-20. Details PubMed Open Access PDF

Westman J, Walpole GFW, Kasper L, Xue BY, Elshafee O, Hube B, Grinstein S (2020) Lysosome fusion maintains phagosome integrity during fungal infection. Cell Host Microbe 28(6), 798-812. Details PubMed Open Access PDF

Chu H, Duan Y, Lang S, Jiang L, Wang Y, Llorente C, Liu J, Mogavero S, Bosques-Padilla F, Abraldes JG, Vargas V, Tu XM, Yang L, Hou X, Hube B, Stärkel P, Schnabl B (2019) The Candida albicans exotoxin Candidalysin promotes alcohol-associated liver disease. J Hepatol 72(3), 391-400. Details PubMed

Correia I, Prieto D, Román E, Wilson D, Hube B, Alonso-Monge R, Pla J (2019) Cooperative role of MAPK pathways in the interaction of Candida albicans with the host Epithelium. Microorganisms 8(1), 48. Details PubMed Open Access PDF

Drummond RA, Swamydas M, Oikonomou V, Zhai B, Dambuza IM, Schaefer BC, Bohrer AC, Mayer-Barber KD, Lira SA, Iwakura Y, Filler SG, Brown GD, Hube B, Naglik JR, Hohl TM, Lionakis MS (2019) CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment. Nat Immunol 20(5), 559-570. Details PubMed Open Access PDF

Graf K, Last A, Gratz R, Allert S, Linde S, Westermann M, Gröger M, Mosig AS, Gresnigt MS, Hube B (2019) Keeping Candida commensal: How lactobacilli antagonize pathogenicity of Candida albicans in an in vitro gut model. Dis Model Mech 12(9), dmm039719. Details PubMed Open Access PDF Supplement

Ho J, Yang X, Nikou SA, Kichik N, Donkin A, Ponde NO, Richardson JP, Gratacap RL, Archambault LS, Zwirner CP, Murciano C, Henley-Smith R, Thavaraj S, Tynan CJ, Gaffen SL, Hube B, Wheeler RT, Moyes DL, Naglik JR (2019) Candidalysin activates innate epithelial immune responses via epidermal growth factor receptor. Nat Commun 10(1), 2297. Details PubMed Open Access PDF

Naglik JR, Gaffen SL, Hube B (2019) Candidalysin: Discovery and function in Candida albicans infections. Curr Opin Microbiol 52, 100-109. (Review) Details PubMed Open Access PDF

Pekmezovic M, Mogavero S, Naglik JR, Hube B (2019) Host-pathogen interactions during female genital tract infections. Trends Microbiol 27(12), 982-996. (Review) Details PubMed

Swidergall M, Khalaji M, Solis N, Moyes D, Drummond R, Hube B, Lionakis M, Murdoch C, Filler S, Naglik J (2019) Candidalysin is required for neutrophil recruitment and virulence during systemic Candida albicans infection. J Infect Dis 220(9), 1477-1488. Details PubMed Open Access PDF

Westman J, Hube B, Fairn GD (2019) Integrity under stress: Host membrane remodelling and damage by fungal pathogens. Cell Microbiol 21(4), e13016. Details PubMed Open Access PDF

Allert S*, Förster TM*, Svensson CM, Richardson JP, Pawlik T, Hebecker B, Rudolphi S, Juraschitz M, Schaller M, Blagojevic M, Morschhäuser J, Figge MT, Jacobsen ID, Naglik JR, Kasper L, Mogavero S, Hube B; *authors contributed equally (2018) Candida albicans-induced epithelial damage mediates translocation through intestinal barriers. mBio 9(3), e00915. Details PubMed Open Access

Kasper L, König A, Koenig PA, Gresnigt MS, Westman J, Drummond RA, Lionakis MS, Groß O, Ruland J, Naglik JR, Hube B (2018) The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes. Nat Commun 9(1), 4260. Details PubMed Open Access

Lazić J, Ajdačić V, Vojnovic S, Zlatović M, Pekmezovic M, Mogavero S, Opsenica I, Nikodinovic-Runic J (2018) Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction. Appl Microbiol Biotechnol 102(4), 1889-1901. Details PubMed PDF

Richardson JP, Mogavero S, Moyes DL, Blagojevic M, Krüger T, Verma AH, Coleman BM, De La Cruz Diaz J, Schulz D, Ponde NO, Carrano G, Kniemeyer O, Wilson D, Bader O, Enoiu SI, Ho J, Kichik N, Gaffen SL, Hube B, Naglik JR (2018) Processing of Candida albicans Ece1p is critical for Candidalysin maturation and fungal virulence. mBio 9(1), e02178-17. Details PubMed Open Access PDF

Richardson JP, Willems HME, Moyes DL, Shoaie S, Barker KS, Tan SL, Palmer GE, Hube B, Naglik JR, Peters BM (2018) Candidalysin drives epithelial signaling, neutrophil recruitment, and immunopathology at the vaginal mucosa. Infect Immun 86(2), e00645-17. Details PubMed Open Access PDF

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 (2016) Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature 532(7597), 64-68. Details PubMed Open Access

Wilson D, Naglik JR, Hube B (2016) The missing link between Candida albicans hyphal morphogenesis and host cell damage. PLOS Pathog 12(10), e1005867. (Review) Details PubMed

Mech F, Wilson D, Lehnert T, Hube B, Figge MT (2014) Epithelial invasion outcompetes hypha development during Candida albicans infection as revealed by an image-based systems biology approach. Cytometry A 85(2), 126-139. Details PubMed

Wilson D, Mayer FL, Miramón P, Citiulo F, Slesiona S, Jacobsen ID, Hube B (2014) Distinct roles of Candida albicans-specific genes in host-pathogen interactions. Eukaryot Cell 13(8), 977-989. Details PubMed

Martin R, Moran GP, Jacobsen ID, Heyken A, Domey J, Sullivan DJ, Kurzai O, Hube B (2011) The Candida albicans-specific gene EED1 encodes a key regulator of hyphal extension. PLOS One 6(4), e18394. Details PubMed

Martin R, Wächtler B, Schaller M, Wilson D, Hube B (2011) Host-pathogen interactions and virulence-associated genes during Candida albicans oral infections. Int J Med Microbiol 301(5), 417-422. (Review) Details PubMed

Wächtler B, Wilson D, Haedicke K, Dalle F, Hube B (2011) From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells. PLOS One 6(2), e17046. Details PubMed Open Access

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