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Establishment of an In vitro System to Study Intracellular Behavior of Candida glabrata in Human THP-1 Macrophages
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Infection-induced glucose starvation triggers NINJ1-dependent macrophage lysis and Candida escape

Harshini Weerasinghe1, Orawan Tulyaprawat1, Helen Stölting1,2

  • 1Department of Biochemistry and Molecular Biology, Infection Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

Nature Communications
|June 10, 2026
PubMed

Insights

Fungal pathogens like Candida cause macrophage death by depleting glucose and activating NINJ1, leading to membrane rupture. Alanine supplementation rescues macrophages by inhibiting NINJ1, impacting fungal escape and immune response.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Pathogens and host immune cells, like macrophages, compete for glucose.
  • This competition disrupts host glycolysis, impairs antimicrobial defenses, and leads to macrophage death.
  • Major fungal pathogens, including Candida albicans and Candida auris, induce this glucose starvation.

Purpose of the Study:

  • To elucidate the mechanism by which fungal pathogens induce macrophage death via glucose starvation.
  • To identify the key host cell death factors involved in fungal-induced macrophage damage.
  • To investigate the role of the amino acid alanine in mitigating this damage and its impact on fungal pathogenesis.

Main Methods:

  • Investigated macrophage lysis induced by Candida albicans and Candida auris under glucose-starved conditions.
  • Examined the role of NINJ1 (a membrane rupture executioner) in glucose starvation-induced cell death.
  • Assessed the protective effect of alanine supplementation on glucose-starved macrophages.
  • Analyzed C. albicans infection effects on host amino acid metabolism in vivo (mice).

Main Results:

  • Glucose starvation by Candida species activates NINJ1, causing macrophage membrane rupture independently of known cell death pathways.
  • NINJ1 is identified as the primary effector of fungal-induced macrophage damage.
  • Alanine supplementation effectively rescues glucose-starved macrophages by inhibiting NINJ1 oligomerization.
  • C. albicans infection alters amino acid metabolism in mice, reducing serum alanine levels.
  • NINJ1-mediated rupture facilitates fungal (Candida) escape from macrophages, associated with candidalysin.

Conclusions:

  • Established the mechanism of NINJ1-mediated macrophage damage triggered by glucose starvation from fungal pathogens.
  • Demonstrated that NINJ1 activation is crucial for fungal-induced macrophage lysis and subsequent fungal egress.
  • Highlighted the protective role of alanine against fungal-induced macrophage death and its potential therapeutic implications.
  • Underscored the interplay between host glucose metabolism, cell death pathways, and fungal virulence strategies.

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