Project C3

Intrinsic modulation of neutrophil antifungal activity against Candida albicans

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 bloodstream infection. Results of project C3 from the first funding period have confirmed the central role of polymorphonuclear leukocytes (PMN) in the defense against invasive fungal infections. Importantly, these findings also corroborate the hypothesis that PMN activation is largely determined by intrinsic mediators like C5a, which is required for both early PMN activation during infection and activation of bystander PMN that are not in direct physical contact with the invading pathogen. We provide evidence that PMN activation is specific to the pathogen and differs not only between fungi of different genera (Candida albicans and Aspergillus fumigatus) but also between more closely related species (C. albicans and Candida glabrata). Building on these results we will continue to analyze networks of PMN activation focussing on: (i) Communication of PMN within human blood. The interaction of PMN with other components of human blood, including monocytes and NK cells will be further dissected. To identify important signaling pathways, we will extend comparative analyses with C. glabrata while continuing comparative analyses with A. fumigatus. A new focus will be directed at the role of human platelets in providing secondary stimuli for PMN activation. (ii) Pathogen specific activation of PMN. Work in the first funding period revealed that PMN induce distinct patterns of activation in response to different fungal pathogens. Making use of C. albicans and C. glabrata as model organisms we aim to dissect the molecular basis for this differential recognition and response. This “intra-genus” comparison will be complemented by a continuation of comparative analyses with A. fumigatus. (iii) PMN activation and fungal immune escape. We will continue to elucidate the novel immune escape mechanism that enables the persistence of viable extracellular C. albicans cells in human blood for prolonged time periods. Initial work suggested a central role of PMN in the removal of host proteins that mediate fungal recognition including C3b and iC3b and we now aim to dissect the molecular mechanisms underlying this cellular remodeling.

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
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 Frontiers
Hünniger K, Kurzai O 2018 Phagocytes as central players in the defence against invasive fungal infection. Semin Cell Dev Biol pii: S1084-9521(17)30540-2 [Epub ahead of print] 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
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
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(2): 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