Project C3

Intrinsic modulation of neutrophil antifungal activity against Candida albicans

Polymorphonuclear neutrophils (PMNs) are of critical importance in the defense against invasive fungal infections. Consequently, neutropenia is an independent risk factor for the development of invasive aspergillosis and carries an increased risk for disseminated infection and impaired outcome in Candida blood-stream infection. Results from the last funding period have confirmed the central role of PMNs in the defense against invasive fungal infections and identified new factors that govern activation of PMNs, thus further dissecting relevant immune effector networks. Building on these results, we will continue to analyze networks of PMN activation in three work packages, and plan to expand our focus on the translational possibilities of our model system: Activation of PMNs by C. albicans is directly linked to immune escape of fungal cells in human blood. Preliminary data generated in the last funding period suggest that surface remodeling of extracellular C. albicans cells is mediated by PMN-derived EVs. The molecular mechanisms of host-dependent immune escape will be analyzed in WP1. In WP2 we aim to dissect the impact of antifungal treatment on immune recognition of both C. albicans and C. glabrata in human blood. A specific focus will be placed on resistant versus susceptible clinical isolates in the context of antifungal therapy. Finally, in WP3 we aim to mimic patient relevant settings in our ex vivo human whole-blood infection model. Using chemical blocking of NADPH oxidase, we will functionally address alterations in patients suffering from chronic granulomatous disease and compare these data with patient derived datasets generated in the last funding period.

High throughput single cell imaging using the ImageStream to analyze immune cell – Candida albicans interactions.
High throughput single cell imaging using the ImageStream to analyze immune cell – Candida albicans interactions.
Principal Investigator
Prof. Dr. Oliver Kurzai
Prof. Dr. Oliver Kurzai

Institute for Hygiene and Microbiology

Julius Maximilians University Würzburg

okurzai@hygiene.uni-wuerzburg.de

Publications
Author Year Title Journal Links
Garbe E, Thielemann N, Hohner S, Kumar A, Vylkova S, Kurzai O, Martin R. 2023 Functional analysis of the Candida albicans ECE1 Promoter. Microbiol Spectr: e0025323 PubMed
Häder, A, Schäuble, S, Gehlen, J, Thielemann N, Buerfent BC, Schüller V, Hess T, Wolf T, Schröer J, Weber M, Hünniger K, Löffler J, Vylkova S, Panagiotou G, Schumacher J, Kurzai O 2023 Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity. Nature Communications PubMed
Mirhakkak MH, Chen X, Ni Y, Heinekamp T, Sae-Ong T, Xu LL, Kurzai O, Barber AE, Brakhage AA, Boutin S, Schäuble S, Panagiotou G 2023 Genome-scale metabolic modeling of Aspergillus fumigatus strains reveals growth dependencies on the lung microbiome. Nat Commun. 14(1):4369 PubMed
Zoran T, Seelbinder B, White PL, Price JS, Kraus S, Kurzai O, Linde J, Häder A, Loeffler C, Grigoleit GU, Einsele H, Panagiotou G, Loeffler J, Schäuble S 2022 Molecular Profiling Reveals Characteristic and Decisive Signatures in Patients after Allogeneic Stem Cell Transplantation Suffering from Invasive Pulmonary Aspergillosis. J Fungi (Basel) 8(2):171 PubMed
Belyaev I, Marolda A, Praetorius J-P, Sarkar A, Medyukhina A, Hünniger K, Kurzai O, Figge MT 2022 Automated Characterisation of Neutrophil Activation Phenotypes in Ex Vivo Human Candida Blood Infections. Computational and Structural Biotechnology Journal PubMed
Seif M, Kakoschke TK, Ebel F, Bellet MM, Trinks N, Renga G, Pariano M, Romani L, Tappe B, Espie D, Donnadieu E, Hünniger K, Häder A, Sauer M, Damotte D, Alifano M, White PL, Backx M, Nerreter T, Machwirth M, Kurzai O, Prommersberger S, Einsele H, Hudecek M, Löffler J 2022 CAR T cells targeting Aspergillus fumigatus are effective at treating invasive pulmonary aspergillosis in preclinical models. Science Transl Med 14: 664 Sciene Transl Med
Tappe B, Lauruschkat CD, Strobel L, Pantaleón García J, Kurzai O, Rebhan S, Kraus S, Pfeuffer-Jovic E, Bussemer L, Possler L, Held M, Hünniger K, Kniemeyer O, Schäuble S, Brakhage AA, Panagiotou G, White PL, Einsele H, Löffler J, Wurster S. 2022 COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds. Front Immunol. 13: 954985 PubMed
Machata S, Sreekantapuram S, Hünniger K, Kurzai O, Dunker C, Schubert K, Krüger W, Schulze-Richter B, Speth C, Rambach G, Jacobsen ID 2021 Significant differences in host-pathogen interactions between murine and human whole blood. Front Immunol 11: 3489 Frontiers
Lehnert T, Leonhardt I, Timme S, Thomas-Rüddel D, Bloos F, Sponholz C, Kurzai O, Figge MT, Hünniger K 2021 Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions. Sci Rep 11: 12039 PubMed
Kämmer P, McNamara S, Wolf T, Conrad T, Allert S, Gerwien F, Hünniger K, Kurzai O, Guthke R, Hube B, Linde J, Brunke S 2021 Survival strategies of pathogenic Candida species in human blood show independent and specific adaptations. mBio 11: e02435-20 PubMed
Lehnert T, Prauße MTE, Hünniger K, Praetorius JP, Kurzai O, Figge MT 2021 Comparative assessment of immune evasion mechanisms in human whole-blood infection assays by a systems biology approach. PLoS One 16: e0249372 PubMed
Barber AE, Sae-Ong T, Kang K, Seelbinder B, Li J, Walther G, Panagiotou G, Kurzai O 2021 Aspergillus fumigatus pan-genome analysis identifies genetic variants associated with human infection. Nat Microbiol 6: 1526–36 PubMed
Mottola A, Ramírez-Zavala B, Hünniger K, Kurzai O, Morschhäuser J 2021 The zinc cluster transcription factor Czf1 regulates cell wall architecture and integrity in Candida albicans. Mol Microbiol. 116(2): 483-497. PubMed
Marolda A, Hünniger K, Böttcher S, Vivas W, Löffler J, Figge MT, Kurzai O 2020 Candida species-dependent release of IL-12 by dendritic cells induces different levels of NK cell stimulation. J Infect Dis 221: 2060-71 PubMed
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: e00206-20 PubMed
Arend N, Pittner A, Ramoji A, Mondol AS, Dahms M, Rüger J, Kurzai O, Schie IW, Bauer M, Popp J, Neugebauer U 2020 Detection and differentiation of bacterial and fungal Infection of neutrophils from peripheral blood using raman spectroscopy. Anal Chem 92: 10560-8 PubMed
Weiss E, Schlegel J, Terpitz U, Weber M, Linde J, Schmitt AL, Hünniger K, Marischen L, Gamon F, Bauer J, Löffler C, Kurzai O, Morton CO, Sauer M, Einsele H, Loeffler J 2020 Reconstituting NK cells after allogeneic stem cell transplantation show impaired response to the fungal pathogen Aspergillus fumigatus. Front Immunol 11: 2117 Frontiers
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: e02435-20 PubMed
Barber A, Riedel J, Sae-Ong T, Kang K, Brabetz W, Panagiotou G, Deising H, Kurzai O 2020 Effects of agricultural fungicide use on Aspergillus fumigatus abundance, antifungal susceptibility, and population structure. mBio 11: e02213-20 PubMed
von Müller C, Bulman F, Wagner L, Rosenberger D, Marolda A, Kurzai O, Eißmann P, Jacobsen ID, Perner B, Hemmerich P, Vylkova S 2020 Active neutrophil responses counteract Candida albicans burn wound infection of ex vivo human skin explants. Sci Rep 10: 21818 PubMed
Lehnert T, Leonhardt I, Timme S, Thomas-Rüddel D, Bloos F, Sponholz C, Kurzai O, Figge MT, Hünniger K 2020 Ex vivo immune profiling in patient blood enables quantification of innate immune effector functions. bioRxiv bioRxiv
Vivas W, Leonhardt I, Hünniger K, Häder A, Marolda A, Kurzai O 2019 Multiple signaling pathways involved in human dendritic cell maturation are affected by the fungal quorum-sensing molecule farnesol. J Immunol 203: 2959-69 J Immunol
Zoran T, Weber M, Springer J, White L, Bauer J, Schober A, Löffler C, Seelbinder B, Hünniger K, Kurzai O, Scherag A, Schäuble S, Morton CO, Einsele H, Linde J, Löffler J 2019 Treatment with etanercept and low monocyte concentration contribute to the risk of invasive aspergillosis in patients post allogeneic stem cell transplantation. Sci Rep 9: 17231 PubMed
Springer J, Walther G, Rickerts V, Hamprecht A, Willinger B, Teschner D, Einsele H, Kurzai O, Loeffler J 2019 Detection of Fusarium species in clinical specimens by probe-based real-time PCR. J Fungi (Basel) 5: E105 PubMed
von Lilienfeld-Toal M, Wagener J, Einsele H, Cornely OA, Kurzai O 2019 Invasive Fungal Infection. Dtsch Arztebl Int 116: 271-278 (Review) PubMed
Al-Zaben N, Medyukhina A, Dietrich S, Marolda A, Hünniger K, Kurzai O, Figge MT 2019 Automated tracking of label-free cells with enhanced recognition of whole tracks. Sci Rep 9: 3317 PubMed
Polke M, Leonhardt I, Kurzai O, Jacobsen ID 2018 Farnesol signalling in Candida albicans - more than just communication. Crit Rev Microbiol 44: 230-43 (Review) PubMed
Morton CO, Wurster S, Fliesser M, Ebel F, Page L, Hünniger K, Kurzai O, Schmitt AL, Michel D, Springer J, Einsele H, Loeffler J 2018 Validation of a simplified in vitro Transwell® model of the alveolar surface to assess host immunity induced by different morphotypes of Aspergillus fumigatus. Int J Med Microbiol 308: 1009-17 PubMed
Prauße MTE, Lehnert T, Timme S, Hünniger K, Leonhardt I, Kurzai O, Figge MT 2018 Predictive virtual infection modeling of fungal immune evasion in human whole blood. Front Immunol 9: 560 Frontiers
Timme S, Lehnert T, Prauße MTE, Hünniger K, Leonhardt I, Kurzai O, Figge M 2018 Quantitative simulations predict treatment strategies against fungal infections in virtual neutropenic patients. Front Immunol 9: 667 PubMed
Hünniger K, Kurzai O 2018 Phagocytes as central players in the defence against invasive fungal infection. Semin Cell Dev Biol 89: 3-15 (Review) PubMed
Weiss E, Ziegler S, Fliesser M, Schmitt AL, Hünniger K, Kurzai O, Morton CO, Einsele H, Loeffler L 2018 First insights in NK-DC cross-talk and the importance of soluble factors during infection with Aspergillus fumigatus. Front Cell Infect Microbiol 8: 288 PubMed
Voltersen V, Blango MG, Herrmann S, Schmidt F, Heinekamp T, Strassburger M, Krüger T, Bacher P, Lother J, Weiss E, Hünniger K, Liu H, Hortschansky P, Scheffold A, Löffler J, Krappmann S, Nietzsche S, Kurzai O, Einsele H, Kniemeyer O, Filler SG, Reichard U, Brakhage AA 2018 Proteome analysis reveals the conidial surface protein CcpA essential for virulence of the pathogenic fungus Aspergillus fumigatus. mBio 9: e01557-18 PubMed
Ziegler S, Weiss E, Schmitt AL, Schlegel J, Burgert A, Terpitz U, Sauer M, Moretta L, Sivori S, Leonhardt I, Kurzai O, Einsele H, Loeffler J 2017 CD56 is a pathogen recognition receptor on human natural killer cells. Sci Rep 7: 6138 PubMed
Dix A, Czakai K, Leonhardt I, Schäferhoff K, Bonin M, Guthke R, Einsele H, Kurzai O, Löffler J, Linde J 2017 Specific and novel microRNAs are regulated as response to fungal infection in human dendritic cells. Front Microbiol 8: 270 PubMed
Pohlers S, Martin R, Krüger T, Hellwig D, Hänel F, Kniemeyer O, Saluz HP, Van Dijck P, Ernst JF, Brakhage A, Mühlschlegel FA, Kurzai O 2017 Lipid signaling via Pkh1/2 regulates fungal CO2 sensing through the kinase Sch9. mBio 8: e02211-16 PubMed
Brandes S, Dietrich S, Hünniger K, Kurzai O, Figge MT 2017 Migration and interaction tracking for quantitative analysis of phagocyte-pathogen confrontation assays. Med Image Anal 356: 172-83 PubMed
Böhringer M, Pohlers S, Schulze S, Albrecht-Eckardt D, Piegsa J, Weber M, Martin R, Hünniger K, Linde J, Guthke R, Kurzai O 2016 Candida albicans infection leads to barrier breakdown and a MAPK/NF-κB mediated stress response in the intestinal epithelial cell line C2BBe1. Cell Microbiol 18: 889-904 Cell Microbiol
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: 64-8 PubMed
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 PubMed
Czakai K, Leonhardt I, Dix A, Bonin M, Linde J, Einsele H, Kurzai O, Loeffler J 2016 Krüppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans Sci Rep 6: 27990 PubMed
Beitzen-Heineke A, Bouzani M, Schmitt A, Kurzai O, Hünniger K, Einsele H, Loeffler J 2016 Human invariant natural killer T cells possess immune-modulating functions during Aspergillus infection. Med Mycol 54: 169-76 PubMed
Dix A, Hünniger K, Weber M, Guthke R, Kurzai O, Linde J 2015 Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study. Front Microbiol 6: 171 PubMed
Linde J, Duggan S, Weber M, Horn F, Sieber P, Hellwig D, Riege K, Marz M, Martin R, Guthke R, Kurzai O 2015 Defining the transcriptomic landscape of Candida glabrata by RNA-Seq. Nucleic Acids Res 43: 1392-406 PubMed
Duggan S, Leonhardt I, Hünniger K, Kurzai O 2015 Host response to Candida albicans bloodstream infection and sepsis. Virulence 6: 316-26 PubMed
Leonhardt I, Spielberg S, Weber M, Albrecht-Eckardt D, Bläss M, Claus R, Barz D, Scherlach K, Hertweck C, Löffler J, Hünniger K, Kurzai O 2015 The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity. mBio 6: e00143 PubMed
Hünniger K, Bieber K, Martin R, Lehnert T, Figge MT, Löffler J, Guo RF, Riedemann NC, Kurzai O 2015 A second stimulus required for enhanced antifungal activity of human neutrophils in blood is provided by anaphylatoxin C5a. J Immunol 194: 1199-210 PubMed
Brandes S, Mokhtari Z, Essig F, Hünniger K, Kurzai O, Figge MT 2015 Automated segmentation and tracking of non-rigid objects in time-lapse microscopy videos of polymorphonuclear neutrophils. Med Image Anal 20: 34-51 PubMed
Duggan S, Essig F, Hünniger K, Mokhtari Z, Bauer L, Lehnert T, Brandes S, Häder A, Jacobsen ID, Martin R, Figge MT, Kurzai O 2015 Neutrophil activation by Candida glabrata but not Candida albicans promotes fungal uptake by monocytes. Cell Microbiol 17: 1259-76 PubMed
Lehnert T, Timme S, Pollmächer J, Hünniger K, Kurzai O, Figge MT 2015 Bottom-up modeling approach for the quantitative estimation of parameters in pathogen-host interactions. Front Microbiol 6: 608 PubMed
Fliesser M, Morton O, Bonin M, Ebel F, Hünniger K, Kurzai O, Einsele H, Löffler J 2015 Hypoxia-inducible factor 1α modulates metabolic activity and cytokine release in anti-Aspergillus fumigatus immune responses initiated by human dendritic cells. Int J Med Microbiol 305: 865-73 PubMed
Hünniger K, Lehnert T, Bieber K, Martin R, Figge MT, Kurzai O 2014 A virtual infection model quantifies innate effector mechanisms and Candida albicans immune escape in human blood. PLoS Comput Biol 10: e1003479 PubMed
Jacobsen ID, Lüttich A, Kurzai O, Hube B, Brock M 2014 In vivo imaging of disseminated murine Candida albicans infection reveals unexpected host sites of fungal persistence during antifungal therapy. J Antimicrob Chemother 69: 2785-96 PubMed
Wartenberg A, Linde J, Martin R, Schreiner M, Horn F, Jacobsen ID, Jenull S, Wolf T, Kuchler K, Guthke R, Kurzai O, Forche A, d'Enfert C, Brunke S, Hube B 2014 Microevolution of Candida albicans in macrophages restores filamentation in a nonfilamentous mutant. PLoS Genet 10: e1004824 PubMed