Project A2

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

Project Description

In contrast to most bacterial pathogens, Aspergillus fumigatus undergoes major morphological changes during the early phase of infection, resulting in different fungal surface structures. Cells of the innate immune system recognize the fungus and its different morphologies by distinct ‘Pattern-Recognition-Receptors’ (PRR), which induce cell specific as well as general defence mechanisms. Important cells of the initial innate immune response include alveolar epithelia, alveolar macrophages, neutrophilic granulocytes and dendritic cells (DCs). Recent data, however, suggest a major contribution of additional innate immune effector cells, such as natural killer cells (NK cells). During invasion of the fungus into the blood vessels and its hematogenous dissemination, neither the different lines of host defence nor the inflammatory background of the various patients are well characterised. Therefore, this project aims at comprehensively characterising the function of different lines of defence (DC sub-populations, alveolar epithelia, NK cells) against A. fumigatus in healthy individuals as well as in immunocompromised patients and, moreover, at identifying factors (immunosuppression, genetic factors, interaction with other effectors of the innate and of the adaptive immune system) that promote or interfere with the antifungal activity of innate immune effector cells. For this purpose, we will study the interplay of immune cells from healthy (and later from immunosuppressed donors) with different fungal morphotypes, focusing on (i) receptor-ligand interactions, (ii) the mode of action of the involved innate immune cell populations as well as (iii) the signalling pathways induced by this interaction. Based on experiments carried out in parallel with the different fungal species, A. fumigatus and Candida albicans, and on comparative analyses of the respective human and fungal transcriptomes, we will identify genes, especially immune response genes, which are either cell-type specifically regulated or similarly regulated in different cells of the innate immune system (epithelia, DCs, NK cells). Our study will also contribute to identify genetic markers among candidate genes, which are potentially associated with a higher risk to develop invasive aspergillosis. In addition, we will study the cross talk between distinct innate immune effector cells and investigate by which means this interaction modulates the response towards A. fumigatus. In the long run, based on the findings derived from the functional analyses of DCs and NK cells towards A. fumigatus, we will develop GMP-grade protocols for the generation of DCs and NK cells suitable for clinical use.

Human dendritic cells with Aspergillus fumigatus (A) conidia and (B) germ tubes (REM, 5000x)

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
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
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
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
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
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
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
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
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
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 myw105

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 pii: S1438-4221(16)30199-0

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 doi: 10.1038/leu.2017.41 [Epub ahead of print] 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