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

Weerasinghe, H; Tulyaprawat, O; Stolting, H; Sonnberger, J; Mobbs, B; Nickson, J; Lange, T; van Denderen, B; Lo, TL; Schille, TB; Olivier, FAB; Kapoor-Kaushik, N; Gottschalk, TA; Hall, C; Silke, J; Vince, JE; Lawlor, KE; Broer, S; Schroder, K; Burgener, SS; Hube, B; Naderer, T; Rose, AJ; Traven, A

Author(s): Weerasinghe, H; Tulyaprawat, O; Stolting, H; Sonnberger, J; Mobbs, B; Nickson, J; Lange, T; van Denderen, B; Lo, TL; Schille, TB; Olivier, FAB; Kapoor-Kaushik, N; Gottschalk, TA; Hall, C; Silke, J; Vince, JE; Lawlor, KE; Broer, S; Schroder, K; Burgener, SS; Hube, B; Naderer, T; Rose, AJ; Traven, A;
Journal Title: Nature Communications
Abstract: Pathogens compete for glucose with macrophages, which disrupts host glycolysis, modulates antimicrobial responses and causes macrophage death. We show that glucose starvation induced by major fungal pathogens Candida albicans and Candida auris causes macrophage lysis by activating NINJ1, the executioner of membrane rupture during cell death. In glucose-starved macrophages, NINJ1 ruptures membranes independently of known cell death programs. Consistently, NINJ1 is the dominant effector of fungal-induced macrophage damage amongst host cell death factors. Supplementation of the amino acid alanine rescues glucose-starved macrophages better than glucose, and it does so by inhibiting NINJ1 oligomerization. Moreover, C. albicans infection disrupts amino acid metabolism in mice and reduces serum alanine. Finally, NINJ1-mediated membrane rupture enables C. albicans egress from macrophages together with the toxin candidalysin. We establish the mechanism of glucose starvation-induced macrophage damage by NINJ1, and demonstrate the roles of NINJ1 and alanine in immune responses to Candida and fungal escape.
Publisher: Springer Nature
Keywords: Animals; *Glucose/metabolism/deficiency; *Macrophages/metabolism/microbiology/immunology; Mice; *Candida albicans/pathogenicity/immunology; *Cell Adhesion Molecules, Neuronal/metabolism/genetics; *Nerve Growth Factors/metabolism/genetics; *Candidiasis/immunology/microbiology/metabolism; Alanine/metabolism; *Candida; Mice, Inbred C57BL
Research Division(s): Inflammation
PubMed ID: 42270656
Publisher's Version: https://doi.org/10.1038/s41467-026-74195-6
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-026-74195-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-07-30 09:26:03

Last Modified: 2026-07-30 09:27:28