Project A3

In vivo analysis of temporal and spatial disease progression and immune cell recruitment during invasive Aspergillus fumigatus infection

Project A3 aims to uncover the key players of secondary immune defense mechanisms in neutropenic and/or alveolar macrophage-depleted conditions against A. fumigatus to uncover how these cells contribute to the regulation of inflammation and fungal clearance. In the first funding period A3 analyzed in vivo pulmonary A. fumigatus disease progression and the spatiotemporal coordination of first line immune cell responses in clinically relevant immunosuppressed murine models. A3 advanced and established novel optical imaging techniques, particularly in vivo bioluminescence imaging and 3D light sheet fluorescence microscopy with optimized automated image processing and analysis. In the present funding period A3 aims to define A. fumigatus strain-specific lung cytokine response and dissect cytokine/ chemokine receptor-ligand interactions after infection. Furthermore, A3 will explore second-line immune defense mechanisms in neutropenic and/or macrophage depleted mice to understand how second line innate immune cells prime adaptive immunity. To further elucidate the molecular mechanisms involved in in vivo NET formation and the role of antifungal vesicles in NETosis, A3 will extend its imaging tool box to intravital and super-resolution microscopy to unravel A. fumigatus-host myeloid cell interactions at the cellular and molecular level.

Multicolour light sheet fluorescence microscopy (LSFM) of invasive pulmonary Aspergillosis (A. fumigatus in red).
Multicolour light sheet fluorescence microscopy (LSFM) of invasive pulmonary Aspergillosis (A. fumigatus in red).
Principal Investigators
Author Year Title Journal Links
Hassan MIA, Keller M, Hillger M, Binder U, Reuter S, Herold K, Telagathoti A, Dahse HM, Wicht S, Trinks N, Nietzsche S, Deckert-Gaudig T, Deckert V, Mrowka R, Terpitz U, Saluz HP, Voigt K 2021 The impact of episporic modification of Lichtheimia corymbifera on virulence and interaction with phagocytes. Comput Struct Biotechnol J 19: 880-896 PubMed
Yu Y, Wolf AK, Thusek S, Heinekamp T, Bromley M, Krappmann S, Terpitz U, Voigt K, Brakhage AA, Beilhack A 2021 Direct visualization of fungal burden in filamentous fungus-infected silkworms. J Fungi (Basel) 7: 136 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
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
Götz R, Panzer S, Trinks N, Eilts J, Wagener J, Turrà D, Di Pietro A, Sauer M, Terpitz U 2020 Expansion microscopy for cell biology analysis in fungi. Front Microbiol 11: 574 Frontiers
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
Yu Y, Albrecht K, Groll J, Beilhack A 2020 Innovative therapies for invasive fungal infections in preclinical and clinical development. Expert Opin Investig Drugs 29: 961-971 PubMed
Schreiber B, Heil HS, Kamp M, Heinze KG 2018 Live-cell fluorescence imaging with extreme background suppression by plasmonic nanocoatings. Opt Express 26: 21301-13 Optics Express
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
Skrahina V, Brock M, Hube B, Brunke S 2017 Candida albicans Hap43 domains are required under iron starvation but not excess. Front Microbiol 8: 2388 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
Savers A, Rasid O, Parlato M, Brock M, Jouvion G, Ryffel B, Cavaillon JM, Eberl G, Ibrahim-Granet O 2016 Infection-mediated priming of phagocytes protects against lethal secondary Aspergillus fumigatus challenge. PLoS One 11: e0153829 PubMed
Dietl AM, Amich J, Leal S, Beckmann N, Binder U, Beilhack A, Pearlman E, Haas H 2016 Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus. Virulence 7: 465-76 PubMed
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
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
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
Ramachandra S, Linde J, Brock M, Guthke R, Hube B, Brunke S 2014 Regulatory networks controlling nitrogen sensing and uptake in Candida albicans. PLoS One 9: e92734 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