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.
Principal Investigator
Prof. Dr. Oliver Kurzai
Institute for Hygiene and Microbiology
Julius Maximilians University Würzburg
Publications
| Author | Year | Title | Journal | Links |
|---|---|---|---|---|
| Batliner M, Schumacher F, Wigger D, Vivas W, Prell A, Fohmann I, Köhler T, Schempp R, Riedel A, Vaeth M, Fekete A, Kleuser B, Kurzai O, Nieuwenhuizen NE | 2024 | The Candida albicans quorum-sensing molecule farnesol alters sphingolipid metabolism in human monocyte-derived dendritic cells. | mBio 2:e0073224 | PubMed |
| 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 |