Project A2

Interaction of Aspergillus fumigatus with human natural killer cells and dendritic cells

Project A2 investigates the immune response of two major innate immune effector cells, dendritic cells (DCs) and natural killer (NK) cells against Aspergillus fumigatus. We will analyze pattern recognition receptors on NK cells and DCs with a strong focus on the newly described A. fumigatus receptor CD56, signaling pathways downstream of these receptors, and corresponding pathogen-associated molecular patterns on the fungus. In addition to classical immunological and molecular approaches, we make use of on high-resolution microscopy and next-generation sequencing. Furthermore, A2 will analyze the receptor-mediated and cytokine-mediated crosstalk of NK cells with DCs in presence of A. fumigatus. Moreover, the functional role of polymorphisms in genes relevant for NK cell modulation and function will be analyzed. Finally, A2 will characterize the antifungal capacity, cytokine secretion and surface receptor expression of NK cells that are isolated from patients at defined time points after allogeneic stem cell transplantation. This project will continue to identify functional defects of NK cells after allogeneic stem cell transplantation in vitro, thereby highlighting the specific relevance of functional NK-cell immunity for effective immune responses against A. fumigatus.

Time course of the NK cell-A. fumigatus interaction and direct binding of CD56 to the fungus. NK cells were cultured with A. fumigatus germ tubes (MOI 0.5) for 3, 6, 9 and 12 h. CLSM pictures were taken from these co-cultures. CD56 is stained in red; auto-fluorescence is visualized in green.

Principal Investigators
Prof. Dr. Hermann Einsele
Prof. Dr. Hermann Einsele

Faculty of Medicine, Department of Internal Medicine II and Research Center for Infectious Diseases (ZINF)  

Julius Maximilians University Würzburg

einsele_h@klinik.uni-wuerzburg.de

Prof. Dr. Jürgen Löffler
Prof. Dr. Jürgen Löffler

Faculty of Medicine, Department of Internal Medicine II and Research Center for Infectious Diseases (ZINF)  

Julius Maximilians University Würzburg

loeffler_j@klinik.uni-wuerzburg.de

Publications
Author Year Title Journal Links
Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, Rasche L, Hartmann E, Dandekar T, Einsele H, Topp M 2017 Frequency of regulatory T cells determines the outcome of the T cell engaging antibody blinatumomab in patients with B precursor ALL. Leukemia 31: 2181-90 PubMed
Wurster S, Weis P, Page L, Lazariotou M, Einsele H, Ullmann AJ 2017 Quantification of A. fumigatus-specific CD154+ T-cells-preanalytic considerations. Med Mycol 55: 223-7 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
Saraiva JP, Oswald M, Biering A, Röll D, Assmann C, Klassert T, Blaess M, Czakai K, Claus R, Löffler J, Slevogt H, König R 2017 Fungal biomarker discovery by integration of classifiers. BMC Genomics 18: 601 PubMed
Wurster S, Thielen V, Weis P, Walther P, Elias J, Waaga-Gasser AM, Dragan M, Dandekar T, Einsele H, Löffler J, Ullmann, AJ 2017 Mucorales spores induce a proinflammatory cytokine response in human mononuclear phagocytes and harbor no rodlet hydrophobins. Virulence 8: 1708-18 PubMed
Hellmann AM, Lother J, Wurster S, Lutz MB, Schmitt AL, Morton CO, Eyrich M, Czakai K, Einsele H, Loeffler  2017 Human and murine innate immune cell populations display common and distinct response patterns during their in vitro interaction with the pathogenic mould Aspergillus fumigatus. Front Immunol 8: 1716 PubMed
Dix A, Czakai K, Springer J, Fliesser M, Bonin M, Guthke R, Schmitt AL, Einsele H, Linde J, Löffler J 2016 Genome-wide expression profiling reveals S100B as biomarker for invasive Aspergillosis. Front Microbiol 7: 320 PubMed
Teutschbein J, Simon S, Lother J, Springer J, Hortschansky P, Morton CO, Löffler J, Einsele H, Conneally E, Rogers TR, Guthke R, Brakhage AA, Kniemeyer O 2016 Proteomic profiling of serological responses to Aspergillus fumigatus antigens in patients with invasive aspergillosis. J Proteome Res 15: 1580-91 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
Kalleda N, Amich J, Arslan B, Poreddy S, Mattenheimer K, Mokhtari Z, Einsele H, Brock M, Heinze K, Beilhack A 2016 Dynamic immune cell recruitment after murine pulmonary Aspergillus fumigatus infection under different immunosuppressive regimens. Front Microbiol 7: 1107 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
Hefter M, Lother J, Weiss E, Schmitt AL, Fliesser M, Einsele H, Loeffler J 2016 Human primary myeloid dendritic cells interact with the opportunistic fungal pathogen Aspergillus fumigatus via the C type lectin receptor Dectin-1. Med Mycol 55: 573-8 Med Mycol
Chopra M, Biehl M, Steinfatt T, Brandl A, Kums J, Amich J, Vaeth M, Kuen J, Holtappels R, Podlech J, Mottok A, Kraus S, Jordán Garrote AL, Bäuerlein CA, Brede C, Ribecchini E, Fick A, Seher A, Polz J, Ottmüller K, Baker J, Nishikii H, Ritz M, Mattenheimer K, Schwinn S, Winter T, Schäfer V, Krappmann S, Einsele H, Mueller TD, Reddehase MJ, Lutz MB, Männel DN, Berberich-Siebelt F, Wajant H, Beilhack A 2016 Exogenous TNFR2 activation protects from acute GvHD by induction of host Treg expansion. J Exp Med 213: 1881-900 PubMed
Berges C, Kerkau T, Werner S, Wolf N, Winter N, Hünig T, Einsele H, Topp MS, Beyersdorf N 2016 Hsp90 inhibition ameliorates CD4+ T cell-mediated acute graft versus host disease in mice. Immun Inflamm Dis 4: 463-73 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
Czakai K, Dittrich M, Kaltdorf M, Müller T, Krappmann S, Schedler A, Bonin M, Dühring S, Schuster S, Speth C, Rambach G, Einsele H, Dandekar T, Löffler J 2016 Influence of platelet-rich plasma on the immune response of human monocyte-derived dendritic cells and macrophages stimulated with Aspergillus fumigatus. Int J Med Microbiol 307: 95-107 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
Rieber N, Singh A, Carevic M, Öz H, Bouzani M, Amich J, Ost M, Ye Z, Ballbach M, Schäfer I, Mezger M, Klimosch SN, Weber ANR, Handgretinger R, Krappmann S, Liese J, Engeholm M, Schüle R, Salish HR, Marodi L, Speckmann C, Grimbacher B, Ruland J, Brown GD, Beilhack A, Loeffler J, Hartl D 2015 Pathogenic fungi regulate T-cell immunity by inducing neutrophilic myeloid-derived suppressor cells through a Dectin-1/CARD9 and ROS-mediated mechanism. Cell Host Microbe 17: 507-14 PubMed
Mueller-Leisse J, Brueggemann S, Bouzani M, Schmitt AL, Einsele H, Loeffler J 2015 Polymorphonuclear neutrophils and granulocytic myeloid-derived suppressor cells inhibit natural killer cell activity toward Aspergillus fumigatus. Med Mycol 56: 622-9 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
Morton CO, Fliesser M, Dittrich M, Mueller T, Bauer R, Kneitz S, Hope W, Rogers TR, Einsele H, Loeffler J 2014 Gene expression profiles of human dendritic cells interacting with Aspergillus fumigatus in a bilayer model of the alveolar epithelium/endothelium interface. PLoS One 9: e98279 PubMed
Lother J, Breitschopf T, Krappmann S, Morton CO, Bouzani M, Kurzai O, Gunzer M, Hasenberg M, Einsele H, Loeffler J 2014 Human dendritic cell subsets display distinct interactions with the mould Aspergillus fumigatus. Int J Med Microbiol 304: 1160-8 PubMed