Interaction with immune cells

Phagocytes such as macrophages and neutrophils are key players of the innate immune system and represent a crucial line of defense against pathogenic Candida species such as C. albicans and C. glabrata. This is particularly illustrated by the fact that invasive Candida infections rarely occur in healthy hosts, and a compromised immune system is one of the major predisposing factors for disease.

Recognition of Candida cells by phagocytes leads to cytokine production, phagocytosis, and the activation of antimicrobial effector functions to induce killing of the fungus. On the other hand, pathogenic Candida spp. are well adapted to their host and have developed mechanisms to evade or counteract the anti-microbial activities of phagocytes. One of these mechanisms is the adaptation of fungal metabolism to cope with nutrient limitation inside the phagosome. This and other strategies allow C. albicans and C. glabrata to not only survive phagocytosis by macrophages, but even proliferate intracellularly and escape. C. albicans escapes by rapid hyphal growth and host cell damage. In contrast, C. glabrata replicates as yeast cells inside macrophages and persists for days, before macrophages burst and fungal cells are released.

We want to characterize the interaction of C. albicans,C. glabrata, and C. auris with phagocytes. We are especially interested in the fungal factors and activities that help Candida to cope with these immune cells, survive and escape. Moreover, in close collaboration with the Junior Research Group Adaptive Pathogenicity Strategies we investigate how immunotherapy impacts on the interactions between C. albicans and macrophages and mitigates escape of C. albicans from macrophages. Therapies that aim at improving the innate immune system are increasingly recognized as essential in improving the outcome of fungal infections. Particularly interferon-g is a promising candidate due to its potential of improving macrophage microbicidal activity.

Publications

Austermeier S, Kasper L, Westman J, Gresnigt MS (2020) I want to break free - macrophage strategies to recognize and kill Candida albicans, and fungal counter-strategies to escape. Curr Opin Microbiol 58, 15-23. Details PubMed

König A, Hube B, Kasper L (2020) The dual Function of the fungal toxin candidalysin during Candida albicans-macrophage interaction and virulence. Toxins 12(8), 469. Details PubMed Open Access PDF

Sprenger M, Hartung TS, Allert S, Wisgott S, Niemiec MJ, Graf K, Jacobsen ID, Kasper L, Hube B (2020) Fungal biotin homeostasis is essential for immune evasion after macrophage phagocytosis and virulence. Cell Microbiol 22(7), e13197. Details PubMed Open Access PDF

Bacher P, Hohnstein T, Beerbaum E, Röcker M, Blango MG, Kaufmann S, Röhmel J, Eschenhagen P, Grehn C, Seidel K, Rickerts V, Lozza L, Stervbo U, Nienen M, Babel N, Milleck J, Assenmacher M, Cornely OA, Ziegler M, Wisplinghoff H, Heine G, Worm M, Siegmund B, Maul J, Creutz P, Tabeling C, Ruwwe-Glösenkamp C, Sander LE, Knosalla C, Brunke S, Hube B, Kniemeyer O, Brakhage AA, Schwarz C, Scheffold A (2019) Human anti-fungal Th17 immunity and pathology rely on cross-reactivity against Candida albicans. Cell 176(6), 1340-1355. Details PubMed Open Access PDF

Domínguez-Andrés J, Novakovic B, Li Y, Scicluna BP, Gresnigt MS, Arts RJW, Oosting M, Moorlag SJCFM, Groh LA, Zwaag J, Koch RM, Ter Horst R, Joosten LAB, Wijmenga C, Michelucci A, van der Poll T, Kox M, Pickkers P, Kumar V, Stunnenberg H, Netea MG (2019) The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab 29(1), 211-220.e5. 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

Grondman I, Arts RJW, Koch RM, Leijte GP, Gerretsen J, Bruse N, Kempkes RWM, Ter Horst R, Kox M, Pickkers P, Netea MG, Gresnigt MS (2019) Frontline science: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst. J Leukoc Biol 106(1), 11-25. Details PubMed Open Access PDF

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

Ishchuk OP, Ahmad KM, Koruza K, Bojanovič K, Sprenger M, Kasper L, Brunke S, Hube B, Säll T, Hellmark T, Gullstrand B, Brion C, Freel K, Schacherer J, Regenberg B, Knecht W, Piškur J (2019) RNAi as a tool to study virulence in the pathogenic yeast Candida glabrata. Front Microbiol 10, 1679. Details PubMed Open Access PDF

Jaeger M, Matzaraki V, Aguirre-Gamboa R, Gresnigt MS, Chu X, Johnson MD, Oosting M, Smeekens SP, Withoff S, Jonkers I, Perfect JR, van de Veerdonk FL, Kullberg BJ, Joosten LAB, Li Y, Wijmenga C, Netea MG, Kumar V (2019) A genome-wide functional genomics approach identifies susceptibility pathways to fungal bloodstream infection in humans. J Infect Dis 220(5), 862-872. Details PubMed Open Access PDF

Jaeger M, Pinelli M, Borghi M, Constantini C, Dindo M, van Emst L, Puccetti M, Pariano M, Ricaño-Ponce I, Büll C, Gresnigt MS, Wang X, Gutierrez Achury J, Jacobs CWM, Xu N, Oosting M, Arts P, Joosten LAB, van de Veerdonk FL, Veltman JA, Ten Oever J, Kullberg BJ, Feng M, Adema GJ, Wijmenga C, Kumar V, Sobel J, Gilissen C, Romani L, Netea MG (2019) A systems genomics approach identifies SIGLEC15 as a susceptibility factor in recurrent vulvovaginal candidiasis. Sci Transl Med 11(496), eaar3558. Details PubMed PDF

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

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

Assendorp EL, Gresnigt MS, Sprenkeler EGG, Meis JF, Dors N, van der Linden JWM, Henriet SSV (2018) Adjunctive interferon-γ immunotherapy in a pediatric case of Aspergillus terreus infection. Eur J Clin Microbiol Infect Dis 37(10), 1915-1922. 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

Verma AH, Zafar H, Ponde NO, Hepworth OW, Sihra D, Aggor FEY, Ainscough JS, Ho J, Richardson JP, Coleman BM, Hube B, Stacey M, McGeachy MJ, Naglik JR, Gaffen SL, Moyes DL (2018) IL-36 and IL-1/IL-17 drive immunity to oral candidiasis via parallel mechanisms. J Immunol 201(2), 627-634. Details PubMed Open Access PDF

Cassone A, Vecchiarelli A, Hube B (2016) Aspartyl proteinases of eukaryotic microbial pathogens: From eating to heating. PLOS Pathog 12(12), e1005992. (Review) Details PubMed Open Access

Gabrielli E, Sabbatini S, Roselletti E, Kasper L, Perito S, Hube B, Cassone A, Vecchiarelli A, Pericolini E (2016) In vivo induction of neutrophil chemotaxis by secretory aspartyl proteinases of Candida albicans. Virulence 7(7), 819-825. Details PubMed Open Access

Hellwig D, Voigt J, Bouzani M, Löffler J, Albrecht-Eckardt D, Weber M, Brunke S, Martin R, Kurzai O, Hünniger K (2016) Candida albicans induces metabolic reprogramming in human NK cells and responds to perforin with a Zinc depletion response. Front Microbiol 7, 750. Details PubMed Open Access

Gabrielli E, Pericolini E, Luciano E, Sabbatini S, Roselletti E, Perito S, Kasper L, Hube B, Vecchiarelli A (2015) Induction of Caspase-11 by aspartyl proteinases of Candida albicans and implication in promoting inflammatory response. Infect Immun 83(5), 1940-1948. Details PubMed

Kasper L, Seider K, Hube B (2015) Intracellular survival of Candida glabrata in macrophages: immune evasion and persistence. FEMS Yeast Res 15(5), fov042. Details PubMed

Brunke S, Seider K, Fischer D, Jacobsen ID, Kasper L, Jablonowski N, Wartenberg A, Bader O, Enache-Angoulvant A, Schaller M, d’Enfert C, Hube B (2014) One small step for a yeast - Microevolution within macrophages renders Candida glabrata hypervirulent due to a single point mutation. PLOS Pathog 10(10), e1004478. Details PubMed Open Access

Kasper L, Seider K, Gerwien F, Allert S, Brunke S, Schwarzmüller T, Ames L, Zubiria-Barrera C, Mansour MK, Becken U, Barz D, Vyas JM, Reiling N, Haas A, Haynes K, Kuchler K, Hube B (2014) Identification of Candida glabrata genes involved in pH modulation and modification of the phagosomal environment in macrophages. PLOS One 9(5), e96015. Details PubMed Open Access

Miramón P, Dunker C, Kasper L, Jacobsen ID, Barz D, Kurzai O, Hube B (2014) A family of glutathione peroxidases contributes to oxidative stress resistance in Candida albicans. Med Mycol 52(3), 223-239. Details PubMed

Quintin J, Voigt J, van der Voort R, Jacobsen ID, Verschueren I, Hube B, Giamarellos-Bourboulis EJ, van der Meer JW, Joosten LA, Kurzai O, Netea MG (2014) Differential role of NK cells against Candida albicans infection in immunocompetent or immunocompromised mice. Eur J Immunol 44(8), 2405-2414. Details PubMed

Seider K, Gerwien F, Kasper L, Allert S, Brunke S, Jablonowski N, Schwarzmüller T, Barz D, Rupp S, Kuchler K, Hube B (2014) Immune evasion, stress resistance, and efficient nutrient acquisition are crucial for intracellular survival of Candida glabrata within macrophages. Eukaryot Cell 13(1), 170-183. Details PubMed

Voigt J, Hünniger K, Bouzani M, Jacobsen ID, Barz D, Hube B, Löffler J, Kurzai O (2014) Human natural killer cells acting as phagocytes against Candida albicans and mounting an inflammatory response that modulates neutrophil antifungal activity. J Infect Dis 209(4), 616-626. Details PubMed

Miramón P, Kasper L, Hube B (2013) Thriving within the host: Candida spp. interactions with phagocytic cells. Med Microbiol Immunol 202(3), 183-195. (Review) Details PubMed

Pietrella D, Pandey N, Gabrielli E, Pericolini E, Perito S, Kasper L, Bistoni F, Cassone A, Hube B, Vecchiarelli A (2013) Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome. Eur J Immunol 43(3), 679-692. Details PubMed

Cheng SC, Sprong T, Joosten LA, van der Meer JW, Kullberg BJ, Hube B, Schejbel L, Garred P, van Deuren M, Netea MG (2012) Complement plays a central role in Candida albicans-induced cytokine production by human PBMCs. Eur J Immunol 42(4), 993-991004. Details PubMed

Seider K, Brunke S, Schild L, Jablonowski N, Wilson D, Majer O, Barz D, Haas A, Kuchler K, Schaller M, Hube B (2011) The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation. J Immunol 187(6), 3072-3086. Details PubMed

Brunke S, Seider K, Almeida RS, Heyken A, Fleck CB, Brock M, Barz D, Rupp S, Hube B (2010) Candida glabrata tryptophan-based pigment production via the Ehrlich pathway. Mol Microbiol 76(1), 25-47. Details PubMed

Jacobsen ID, Brunke S, Seider K, Schwarzmüller T, Firon A, d'Enfért C, Kuchler K, Hube B (2010) Candida glabrata persistence in mice does not depend on host immunosuppression and is unaffected by fungal amino acid auxotrophy. Infect Immun 78(3), 1066-1077. Details PubMed

Seider K, Heyken A, Lüttich A, Miramón P, Hube B (2010) Interaction of pathogenic yeasts with phagocytes: survival, persistence and escape. Curr Opin Microbiol 13(4), 392-400. (Review) Details PubMed

Staff

Sophie Austermeier

Phone: +49 3641 532-1389 Email: sophie.austermeier@leibniz-hki.de

Dr. Mark S Gresnigt

Phone: +49 3641 532-1305 Email: mark.gresnigt@leibniz-hki.de

Dr. Lydia Kasper

Phone: +49 3641 532-1219 Email: lydia.kasper@leibniz-hki.de

Annika König

Phone: +49 3641-532-1403 Email: annika.koenig@leibniz-hki.de