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

Fungal Infection, especially allergic bronchopulmonary aspergillosis, is a leading cause of infection-associated morbidity and death in patients with cystic fibrosis. We have previously discovered that the new leading treatment in cystic fibrosis, CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor (ETI, Trikafta), drastically reduces the colonization and Infection by Aspergillus fumigatus. However, the reasons for this decrease in patients are not known so far. In this study, we have shown, using A. fumigatus reference strains and strains isolated from patients with cystic fibrosis, that CFTR modulators have no discernible impact on initial conidia growth in vitro. However, in a condition-dependent manner, we demonstrated a decrease in the minimal effective concentration (MEC) of caspofungin when administered with ETI on conidia. By contrast, during macrophage Infection, we observed that high concentrations of ETI treatment promoted Fungal growth but inhibited inflammasome activation.IMPORTANCEThe advent of ETI therapy represents a pivotal moment, signaling the onset of major changes in the medical field of cystic fibrosis and its related infectious diseases. However, the impact of ETI treatment on the patient's microbiota and pathogens has to be further studied as proof arises of changes in patient colonization.

Aspergillus fumigatus; Elexakaftor/Tezacaftor/Ivacaftor; cftr modulators; cystic fibrosis.