Back to publications

2026

Nat Commun. 2026 Jun 10. doi: 10.1038/s41467-026-74195-6. Online ahead of print.

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

Harshini Weerasinghe, Orawan Tulyaprawat, Helen Stölting, Johannes Sonnberger, Byron Mobbs, Joshua Nickson Theresa Lange, Bryce van Denderen, Tricia L Lo, Tim Bastian Schille, Françios A B Olivier, Natasha Kapoor-Kaushik, Timothy A Gottschalk, Cathrine Hall, John Silke, James E Vince, Kate E Lawlor, Stefan Bröer, Kate Schroder, Sabrina Sofia Burgener, Bernhard Hube, Thomas Naderer, Adam J Rose, Ana Traven

Department of Biochemistry and Molecular Biology, Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. Department of Biochemistry and Molecular Biology, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute (HKI), Jena, Germany. Centre for Cell Biology and Chronic Disease, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, Australia. Cluster of Excellence Balance of the Microverse, Friedrich Schiller University, Jena, Germany. Monash Ramaciotti Centre for Cryo-Electron Microscopy, Monash University, Clayton, VIC, Australia. Centre for Innate Immunity and Infectious Diseases at the Hudson Institute of Medical Research, Clayton, VIC, Australia. Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville, VIC, Australia. The Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. Research School of Biology, Australian National University, Canberra, ACT, Australia. Institute of Microbiology, Friedrich Schiller University, Jena, Germany. Department of Biochemistry and Molecular Biology, Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

Service type: Stock strains

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.