The yeast Candida albicans is an important human pathogen in hospital settings, causing serious disease from which mortality is very high. Phagocytosis by macrophages is an important component of the innate immune response to C. albicans. Candida can counteract by switching from yeast to hyphal morphology, whereby hyphal filaments pierce the macrophages, kill them and escape. The current model is that hyphal filaments cause mechanical destruction of the macrophages, but whether this really is the (sole) mechanism of death is not known.
We have devised a new time-lapse microscopy assay to monitor the interaction of C. albicans with macrophages, and used it to show that Candida kills macrophages by at least two mechanisms. Upon phagocytosis, recognition of C. albicans causes a proinflammatory host cell death called pyroptosis. Hyphal morphogenesis is important for triggering pyroptosis. In the absence of the pyroptotic caspases 1 and 11, macrophage killing by C. albicans is impaired despite the formation of hyphal filaments. This demonstrates that mechanical destruction of macrophages by hyphae is not the sole mechanism of killing. We identified a C. albicans mutant that formed hyphae of wild type morphology, but was impaired in causing early macrophage death. Results with this mutant suggest that proper hyphal cell wall organization is necessary for macrophage death in the early phase. The second phase of macrophage killing starts at around 8 hours post phagocytosis under our experimental conditions. For this, hyphal morphogenesis of Candida is important, but the pyroptotic caspases are dispensable, showing that a different mechanism is at play.
We propose a new model: a key function of hyphal structures in causing macrophage death is to trigger pyroptosis. Candida might hijack this immune response to its own advantage, for immune escape.