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Deletion of RAP1 affects iron homeostasis, azole resistance, and virulence in Candida albicans

Summary

Researchers found that a protein called Rap1 plays a critical role in how the dangerous fungus Candida albicans acquires and uses iron, which is essential for its survival in the human body. When the RAP1 gene was deleted, the fungus became much less virulent and lethal in infected mice, while paradoxically becoming more resistant to the antifungal drug fluconazole under iron-limited conditions. These findings suggest that targeting iron acquisition through Rap1 could be a new therapeutic strategy against serious fungal infections.

Background

Rap1 is a DNA-binding protein conserved from yeast to mammals with known roles in telomeric maintenance. Iron is essential for Candida albicans survival in the iron-restricted host environment, and understanding iron homeostasis regulation is critical for understanding C. albicans pathogenesis and virulence.

Objective

To explore additional functions of Candida albicans Rap1 beyond telomere maintenance, particularly investigating its role in iron regulation, azole resistance, and virulence through RNA sequencing analysis and experimental validation.

Results

RAP1 deletion impaired iron acquisition, reduced expression of iron-related genes under low-iron conditions, decreased flavin production by 50%, reduced hemolytic activity, and increased fluconazole resistance particularly under iron-limitation. Notably, RAP1 deletion led to significantly attenuated C. albicans virulence with over 90% mouse survival compared to near-complete mortality with wild-type infection.

Conclusion

C. albicans Rap1 plays novel roles in iron homeostasis, azole resistance, and virulence beyond its known telomeric functions. These findings reveal that Rap1 is particularly important for iron acquisition and utilization under low-iron conditions, and its deletion substantially reduces pathogenicity through altered iron regulation and drug resistance mechanisms.
  • Published in:mSphere,
  • Study Type:Experimental Study,
  • Source: PMID: 40265929
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