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

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 and 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.