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.

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
Publications
Author Year Title Journal Links
Heilig L, Natasha F, Trinks N, Aimanianda V, Wong SSW, Fontaine T, Terpitz U, Strobel L, Le Mauff F, Sheppard DC, Schäuble S, Kurzai O, Hünniger K, Weiss E, Vargas M, Howell PL, Panagiotou G, Wurster S, Einsele H, Loeffler J 2024 CD56-mediated activation of human natural killer cells is triggered by Aspergillus fumigatus galactosaminogalactan. PLoS Pathog. 20(6):e1012315 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
Halder LD, Babych S, Palme DI, Mansouri-Ghahnavieh E, Ivanov L, Ashonibare V, Langenhorst D, Prusty B, Rambach G, Wich M, Trinks N, Blango MG, Kornitzer D, Terpitz U, Speth C, Jungnickel B, Beyersdorf N, Zipfel PF, Brakhage AA, Skerka C 2022 Candida albicans induces cross-kingdom miRNA trafficking in human monocytes to promote fungal growth. mBio 13(1): e0356321 mBio
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
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
Springer J, Held J, Mengoli C, Schlegel PG, Gamon F, Träger J, Kurzai O, Einsele H, Loeffler J, Eyrich M 2021 Diagnostic performance of (1→3)-β-D-Glucan alone and in combination with Aspergillus PCR and Galactomannan in serum of pediatric patients after allogeneic hematopoietic stem cell transplantation. J Fungi 7: 238 PubMed
Lauruschkat CD, Page L, White PL, Etter S, Davies HE, Duckers J, Ebel F, Schnack E, Backx M, Dragan M, Schlegel N, Kniemeyer O, Brakhage AA, Einsele H, Loeffler J, Wurster S 2021 Development of a simple and robust whole blood assay with dual co-stimulation to quantify the release of T-cellular signature cytokines in response to Aspergillus fumigatus antigens. J Fungi 7: 462 MDPI
Page L, Wallstabe J, Lother J, Bauser M, Kniemeyer O, Strobel L, Voltersen V, Teutschbein J, Hortschansky P, Morton CO, Brakhage AA, Topp M, Einsele H, Wurster S, Loeffler J 2021 CcpA- and Shm2-pulsed myeloid dendritic cells induce T-cell activation and enhance the neutrophilic oxidative burst response to Aspergillus fumigatus. Front Immunol 12: 659752 PubMed
Trinks N, Reinhard S, Drobny M, Heilig L, Löffler J, Sauer M, Terpitz U 2021 Subdiffraction-resolution fluorescence imaging of immunological synapse formation between NK cells and A. fumigatus by expansion microscopy. Commun Biol 4: 1151. PubMed
Amich J, Mokhtari Z, Strobel M, Vialetto E, Sheta D, Yu Y, Hartweg J, Kalleda N, Jarick KJ, Brede C, Jordán-Garrote AL, Thusek S, Schmiedgen K, Arslan B, Pinnecker J, Thornton CR, Gunzer M, Krappmann S, Einsele H, Heinze KG, Beilhack A 2020 Three-dimensional light sheet fluorescence microscopy of lungs to dissect local host immune-Aspergillus fumigatus interactions. mBio 11: e02752-19 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
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
Seelbinder B, Wallstabe J, Marischen L, Weiss E, Wurster S, Page L, Löffler C, Bussemer L, Schmitt A, Wolf T, Becker J, Kalinke U, Vogel J, Panagiotou G, Einsele H, Westermann A, Schäuble S, Loeffler J 2020 RNA-seq reveals synergy in a human virus-fungus co-infection model. Cell Rep 33: 108389 PubMed
Lupiañez CB, Martínez-Bueno M, Sánchez-Maldonado JM, Badiola J, Cunha C, Springer J, Lackner M, Segura-Catena J, Canet LM, Alcazar-Fuoli L, López-Nevot MA, Fianchi L, Aguado JM, Pagano L, López-Fernández E, Alarcón-Riquelme M, Potenza L, Gonçalves SM, Luppi M, Moratalla L, Solano C, Sampedro A, González-Sierra P, Cuenca-Estrella M, Lagrou K, Maertens JA, Lass-Flörl C, Einsele H, Vazquez L; PCRAGA Study Group, Loeffler J, Ríos-Tamayo R, Carvalho A, Jurado M, Sainz J 2020 Polymorphisms within the ARNT2 and CX3CR1 genes are associated with the risk of developing invasive Aspergillosis. Infect Immun 88: e00882-19 PubMed
Lauruschkat CD, Page L, Etter S, Weis P, Gamon F, Kraus S, Einsele H, Wurster S, Loeffler J 2020 T-cell immune surveillance in allogenic stem cell transplant recipients: Are whole blood-based assays ready to challenge ELISPOT? Open Forum Infect Dis 8: ofaa547 PubMed
Srivastava M, Bencurova E, Gupta SK, Weiss E, Löffler J, Dandekar T 2019 Aspergillus fumigatus challenged by human dendritic cells: metabolic and regulatory pathway responses testify a tight battle. Front Cell Infect Microbiol 9: 168 PubMed
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
Seif M, Einsele H, Löffler J 2019 CAR T Cells beyond cancer: Hope for immunomodulatory therapy of infectious diseases. Front Immunol 10: 2711 (Review) 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
Belic S, Page L, Lazariotou M, Waaga-Gasser AM, Dragan M, Springer J, Loeffler J, Morton CO, Einsele H, Ullmann AJ, Wurster S 2019 Comparative analysis of inflammatory cytokine release and alveolar epithelial barrier invasion in a Transwell® bilayer model of mucormycosis. Front Microbiol 9: 3204 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
Page L, Weis P, Müller T, Dittrich M, Lazariotou M, Dragan M, Waaga-Gasser AM, Helm J, Dandekar T, Einsele H, Löffler J, Ullmann AJ, Wurster S 2018 Evaluation of Aspergillus and Mucorales specific T-cells and peripheral blood mononuclear cell cytokine signatures as biomarkers of environmental mold exposure. Int J Med Microbiol 308: 1018-26 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
Marischen L, Englert A, Schmitt AL, Einsele H, Loeffler J 2018 Human NK cells adapt their immune response towards increasing multiplicities of infection of Aspergillus fumigatus. BMC Immunol 19: 39 PubMed
Lauruschkat CD, Einsele H, Loeffler J 2018 Immunomodulation as a therapy for Aspergillus Infection: Current status and future perspectives. J Fungi (Basel) 4: 137 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
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: 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