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Updated: Dec 13, 2025
Immunometabolic Circuits in Infection for Advancing Host Directed Therapies
Published on: September 13, 2024
Metabolic competition between host and pathogen dictates inflammasome responses to fungal infection
Timothy M Tucey1, Jiyoti Verma1, Françios A B Olivier1
1Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
Abstract:
The NLRP3 inflammasome has emerged as a central immune regulator that senses virulence factors expressed by microbial pathogens for triggering inflammation. Inflammation can be harmful and therefore this response must be tightly controlled. The mechanisms by which immune cells, such as macrophages, discriminate benign from pathogenic microbes to control the NLRP3 inflammasome remain poorly defined. Here we used live cell imaging coupled with a compendium of diverse clinical isolates to define how macrophages respond and activate NLRP3 when faced with the human yeast commensal and pathogen Candida albicans. We show that metabolic competition by C. albicans, rather than virulence traits such as hyphal formation, activates NLRP3 in macrophages. Inflammasome activation is triggered by glucose starvation in macrophages, which occurs when fungal load increases sufficiently to outcompete macrophages for glucose. Consistently, reducing Candida's ability to compete for glucose and increasing glucose availability for macrophages tames inflammatory responses. We define the mechanistic requirements for glucose starvation-dependent inflammasome activation by Candida and show that it leads to inflammatory cytokine production, but it does not trigger pyroptotic macrophage death. Pyroptosis occurs only with some Candida isolates and only under specific experimental conditions, whereas inflammasome activation by glucose starvation is broadly relevant. In conclusion, macrophages use their metabolic status, specifically glucose metabolism, to sense fungal metabolic activity and activate NLRP3 when microbial load increases. Therefore, a major consequence of Candida-induced glucose starvation in macrophages is activation of inflammatory responses, with implications for understanding how metabolism modulates inflammation in fungal infections.
Insights
Macrophages sense Candida albicans by detecting glucose starvation, not virulence factors. This metabolic competition activates the NLRP3 inflammasome, driving inflammation without causing cell death.
Area of Science:
- Immunology
- Microbiology
- Metabolic pathways
Background:
- The NLRP3 inflammasome regulates inflammation by sensing microbial threats.
- Understanding how macrophages distinguish between harmless and pathogenic microbes is crucial for controlling immune responses.
- The role of metabolic cues in inflammasome activation during fungal infections is not well understood.
Purpose of the Study:
- To investigate how macrophages respond to Candida albicans and activate the NLRP3 inflammasome.
- To determine the specific microbial factors that trigger inflammasome activation by C. albicans.
- To elucidate the metabolic mechanisms underlying NLRP3 inflammasome activation in macrophages during fungal infections.
Main Methods:
- Live cell imaging was employed to observe macrophage responses to diverse clinical isolates of Candida albicans.
- Metabolic competition, specifically glucose uptake by C. albicans, was analyzed as a trigger for inflammasome activation.
- Experimental conditions were manipulated to alter glucose availability and fungal glucose competition.
Main Results:
- Metabolic competition by C. albicans, leading to glucose starvation in macrophages, activates the NLRP3 inflammasome.
- Hyphal formation and other virulence traits were found to be less significant triggers compared to glucose competition.
- Reducing fungal glucose competition or increasing macrophage glucose availability attenuated inflammatory responses.
- Glucose starvation-induced inflammasome activation leads to cytokine production but not pyroptosis, except under specific conditions.
Conclusions:
- Macrophages utilize their metabolic status, particularly glucose metabolism, to sense microbial load and activate the NLRP3 inflammasome.
- Candida albicans-induced glucose starvation in macrophages is a key driver of inflammatory responses.
- Metabolism plays a critical role in modulating inflammation during fungal infections, with implications for therapeutic strategies.
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