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Deubiquitinase Ubp5 is essential for pulmonary immune evasion and hematogenous dissemination of Cryptococcus neoformans

Summary

This study shows that removing a fungal enzyme called Ubp5 from Cryptococcus neoformans significantly weakens the fungus and allows the body’s immune system to fight the infection more effectively. The fungus without Ubp5 loses its ability to hide from the immune system, triggering stronger protective immune responses including more T cells and beneficial inflammatory signals. This research suggests that targeting Ubp5 could be a promising strategy to help treat cryptococcal infections by enhancing the body’s natural defense mechanisms.

Background

Cryptococcosis is an opportunistic fungal infection with significant mortality, particularly in immunocompromised populations. The outcome of infection depends on the dynamic interaction between fungal virulence factors and host immune responses. Ubiquitination is a critical post-translational modification regulating various cellular processes in pathogenic fungi.

Objective

This study investigates the role of deubiquitinase Ubp5 in modulating host defenses and fungal pathogenesis during Cryptococcus neoformans infections. The aim was to determine how Ubp5 deletion affects pulmonary invasion, extrapulmonary dissemination, and host immune responses.

Results

Ubp5 deletion significantly reduced pulmonary invasion and extrapulmonary dissemination, resulting in prolonged survival and decreased fungal burdens in mice. The attenuated virulence was associated with enhanced host immune responses including lymphocyte-dominated inflammatory infiltration, increased Th1/Th17 cytokine response, and defects in key virulence factors including polysaccharide capsule and melanin. Ubp5 deletion also caused morphological changes including distorted cell shapes and reduced ribosomal particles.

Conclusion

Ubp5 is essential for maintaining cryptococcal virulence through pulmonary immune evasion and hematogenous dissemination. Deletion of Ubp5 compromises fungal pathogenic fitness and promotes protective immune responses. Targeting Ubp5 could enhance host immunity against cryptococcosis by promoting protective immune responses and limiting fungal dissemination.
  • Published in:Mycology,
  • Study Type:In vivo and in vitro experimental study,
  • Source: PMID: 40937134, DOI: 10.1080/21501203.2025.2453739
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