The fungal pathogen Candida albicans causes macrophage death and escapes, but 
the molecular mechanisms remained unknown. Here we used live-cell imaging to 
monitor the interaction of C. albicans with macrophages and show that C. 
albicans kills macrophages in two temporally and mechanistically distinct 
phases. Early upon phagocytosis, C. albicans triggers pyroptosis, a 
proinflammatory macrophage death. Pyroptosis is controlled by the developmental 
yeast-to-hypha transition of Candida. When pyroptosis is inactivated, wild-type 
C. albicans hyphae cause significantly less macrophage killing for up to 8 h 
postphagocytosis. After the first 8 h, a second macrophage-killing phase is 
initiated. This second phase depends on robust hyphal formation but is 
mechanistically distinct from pyroptosis. The transcriptional regulator Mediator 
is necessary for morphogenesis of C. albicans in macrophages and the 
establishment of the wild-type surface architecture of hyphae that together 
mediate activation of macrophage cell death. Our data suggest that the defects 
of the Mediator mutants in causing macrophage death are caused, at least in 
part, by reduced activation of pyroptosis. A Mediator mutant that forms hyphae 
of apparently wild-type morphology but is defective in triggering early 
macrophage death shows a breakdown of cell surface architecture and reduced 
exposed 1,3 β-glucan in hyphae. Our report shows how Candida uses host and 
pathogen pathways for macrophage killing. The current model of mechanical 
piercing of macrophages by C. albicans hyphae should be revised to include 
activation of pyroptosis by hyphae as an important mechanism mediating 
macrophage cell death upon C. albicans infection. IMPORTANCE Upon phagocytosis 
by macrophages, Candida albicans can transition to the hyphal form, which causes 
macrophage death and enables fungal escape. The current model is that the highly 
polarized growth of hyphae results in macrophage piercing. This model is 
challenged by recent reports of C. albicans mutants that form hyphae of 
wild-type morphology but are defective in killing macrophages. We show that C. 
albicans causes macrophage cell death by at least two mechanisms. Phase 1 
killing (first 6 to 8 h) depends on the activation of the pyroptotic programmed 
host cell death by fungal hyphae. Phase 2 (up to 24 h) is rapid and depends on 
robust hyphal formation but is independent of pyroptosis. Our data provide a new 
model for how the interplay between fungal morphogenesis and activation of a 
host cell death pathway mediates macrophage killing by C. albicans hyphae.