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Immunometabolic reprogramming in macrophages infected with active and dormant Cryptococcus neoformans: differential modulation of respiration, glycolysis, and fatty acid utilization

Summary

Researchers discovered that when fungal yeast cells enter a dormant state inside immune cells, they trigger different metabolic changes compared to actively growing yeast. While active yeast pushes immune cells to work harder metabolically, dormant yeast causes minimal stress but increases fat uptake by immune cells. This difference may explain how some fungal infections can remain hidden in the body for long periods without causing symptoms.

Background

Cryptococcus neoformans can exist in dormant viable but not cultivable (VBNC) states within macrophages, which is linked to latent infections. Previous transcriptomic studies revealed differential immune responses between macrophages infected with active versus dormant fungal cells. Understanding these metabolic differences is critical for comprehending how dormant infections persist.

Objective

This study aimed to characterize the immunometabolic adaptations of bone marrow-derived macrophages (BMDM) infected with active versus dormant VBNC Cryptococcus neoformans. The researchers investigated differential modulation of mitochondrial function, respiration, glycolysis, and fatty acid metabolism in response to different fungal growth stages.

Results

Active Cryptococcus induced mitochondrial depolarization, increased glycolysis and oxygen consumption, while VBNC infection caused minimal changes in mitochondrial function. VBNC infection uniquely increased fatty acid uptake and upregulated fatty acid transporter genes (Fabp1, Fabp4) in M1-BMDM. Both fungal forms increased glycolytic gene expression but with differential effects on lipid metabolism pathways.

Conclusion

Active and dormant Cryptococcus neoformans induce distinct immunometabolic reprogramming in macrophages, with VBNC cells causing attenuated metabolic changes while specifically modulating fatty acid metabolism. These differential responses likely reflect adaptation to prolonged intracellular residency and may be relevant to granuloma formation and latent infection persistence.
  • Published in:Infection and Immunity,
  • Study Type:Experimental Research Study,
  • Source: PMID: 39714095, DOI: 10.1128/iai.00487-24
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