Infection-induced glucose starvation triggers NINJ1-dependent macrophage lysis and pathogen escape

Pathogens compete for glucose with macrophages, which disrupts host glycolysis, modulates antimicrobial responses and causes macrophage death. We show that, upon glucose starvation caused by major fungal pathogens Candida albicans and Candida auris , macrophages lyse by activating NINJ1, the executioner of membrane rupture during cell death. In glucose-starved macrophages NINJ1 ruptures membranes independently of known cell death programs. Moreover, among cell death factors, NINJ1 is the dominant effector of fungal-induced macrophage damage. Supplementation of a single amino acid, alanine, rescues macrophages by inhibiting NINJ1 oligomerization, and C. albicans infection disrupts amino acid metabolism in mice and reduces serum alanine. Finally, NINJ1-mediated membrane rupture enables C. albicans egress from macrophage together with the toxin candidalysin. We establish the mechanism of glucose starvation-induced macrophage damage by activation of NINJ1, discover an approach to protect macrophages using a key mammalian metabolite, and demonstrate that NINJ1-dependent pathways are hijacked as an immune escape route.