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Condition-dependent effects of Elexacaftor/Tezacaftor/Ivacaftor (Trikafta) on Aspergillus fumigatus growth

Summary

This study examines how Trikafta, a new cystic fibrosis medication, affects a common fungal lung infection (Aspergillus fumigatus). The researchers found that Trikafta doesn’t directly kill the fungus but does make it more susceptible to antifungal drugs and improves lung clearance. Surprisingly, at high concentrations, the medication actually reduced the immune response against the fungus in immune cells, suggesting the need for careful monitoring of patients on this therapy.

Background

Cystic fibrosis patients treated with CFTR modulators (Elexacaftor/Tezacaftor/Ivacaftor, Trikafta) show reduced Aspergillus fumigatus colonization. However, the mechanisms underlying this reduction remain unclear. Understanding how these modulators interact with A. fumigatus is important for optimizing treatment strategies.

Objective

This study investigated the direct and indirect effects of CFTR modulators on A. fumigatus growth under various conditions. The researchers examined effects on conidia growth, biofilm formation, antifungal drug sensitivity, and macrophage-mediated immune responses.

Results

ETI treatment did not directly inhibit initial conidia growth or biofilm formation at physiologically relevant concentrations. However, ETI reduced the minimal effective concentration of caspofungin against A. fumigatus. In macrophage infections, high concentrations of ETI paradoxically promoted fungal growth while inhibiting inflammasome activation and IL-1β production.

Conclusion

CFTR modulators exert pleiotropic, context-dependent effects on A. fumigatus. The reduction in fungal colonization observed in treated patients is likely due to improved respiratory clearance rather than direct antimicrobial effects. The inhibition of inflammasome activation by ETI warrants further investigation as it may have implications for long-term fungal control.
  • Published in:Microbiology Spectrum,
  • Study Type:Experimental In Vitro and Ex Vivo Study,
  • Source: PMID: 40736245, DOI: 10.1128/spectrum.02275-24
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