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Publications

Journal Article Ahead of print

PubMed: 42290167 DOI: 10.1242/dmm.052865

Transdifferentiated BLaER1 cells as a genetically-tractable model to study the interaction of pathogenic fungi with macrophages.

Dis Model Mech

Authors: Johannes Sonnberger, Erik Böhm, Janik Adriana Tomás-Morales, Theresa Lange, Katrin Bagola, Lisa Denner, Lydia Kasper, Sascha Brunke, Ger van Zandbergen, Jakob L Sprague, Bernhard Hube

Affiliations

  • Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany.
  • Department of Medicine, Health and Medical University Erfurt, 99089 Erfurt, Germany.
  • Division of Immunology, Paul Ehrlich Institute Langen, Langen, Germany.
  • Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany. Institute of Novel and Emerging Infectious Diseases, Friedrich Loeffler Institute, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany.
  • Division of Immunology, Paul Ehrlich Institute Langen, Langen, Germany. Institut for Immunology, University Medical Center, Johannes Gutenberg University, Mainz, Germany. Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University, Mainz, Germany.
  • Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Jena, Germany. Institute of Experimental Biomedicine, Chair I, University Hospital Würzburg, Germany. Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität, Würzburg, Germany.
  • Institute of Microbiology, Friedrich Schiller University, Jena, Germany.
  • Cluster of Excellence, Balance of the Microverse, Friedrich Schiller University, Jena, Germany.

Abstract

Macrophages are essential in the defense against fungal disease. Elucidating antimicrobial mechanisms of macrophages and pathogen activities to evade these phagocytes will help in understanding fungal infections. Existing experimental models, however, have a number of disadvantages. Human macrophage-like cell lines offer genetic tractability, but often display reduced antifungal activity and altered phenotypes compared to primary cells. In contrast, primary human monocyte-derived macrophages closely reflect physiological responses but their use is constrained by donor variability, limited availability, and restricted genetic manipulability. Here, we establish transdifferentiated BLaER1 cells as a human-derived, highly potent, and genetically-tractable infection model to study fungal-host interactions. We show that BLaER1 cells display macrophage characteristics and rapidly phagocytose cells of the major fungal pathogens Candida albicans, C. glabrata or C. auris. BLaER1 cells form functional phagolysosomes and elicit pro-inflammatory immune responses. Using knockout BLaER1 cells, we demonstrate for the first time in a human macrophage model that the host factor gasdermin D and the fungal peptide toxin candidalysin have distinct roles in triggering pyroptosis and inducing lytic host cell death.

MeSH

Cells, Macrophages, Mycoses, Fungi, Infections