The Cystic Fibrosis treatment, Trikafta, affects growth, viability, and cell wall ofAspergillus fumigatusbiofilms

Abstract

ABSTRACTPeople with Cystic Fibrosis (pwCF) commonly test positive for the pathogenic fungus,Aspergillus fumigatus,which is associated with a decline in lung function. Trikafta is a recently approved therapy for pwCF that improves quantity and function of the CFTR protein, however, it is not known how Trikafta affects microbial communities in the lung. Therefore, the aim of this study was to determine whether Trikafta directly affectsA. fumigatusgrowth and biology. While Trikafta did not impact the viability ofA. fumigatusconidia, treatment ofA. fumigatusbiofilms with Trikafta reduced overall biofilm biomass. This finding was associated with increased membrane permeability, decreased viability, and reduced metabolic activity following long-term treatment of biofilms. Trikafta-induced membrane permeability and biomass reduction was partially blocked with the calcium channel inhibitor Verapamil and fully blocked by the mammalian CFTR inhibitor GlyH-101. Trikafta-induced biomass reduction and metabolic activity was shown to be regulated by the High Osmolarity Glycerol (HOG) pathway genesakA. Trikafta treatment also induced resistance to the cell wall stressor calcofluor white, susceptibility to the antifungal caspofungin, and decreased inflammatory responses from murine bone marrow cells. Collectively, these results reveal that Trikafta affects infection-relevantA. fumigatusbiology and host-microbial interactions.IMPORTANCEPeople with Cystic Fibrosis (pwCF) commonly test positive for the pathogenic fungus,Aspergillus fumigatus, which is associated with a decline in lung function. Trikafta is a recently approved therapy for pwCF that improves quantity and function of the CFTR protein, however, it is not known how Trikafta affects microbial communities in the CF lung. Here we report that Trikafta has anti-fungal activity against the infection relevant form ofA. fumigatus, termed biofilms. When exposed to TrikaftaA. fumigatusbiofilms lose their viability. In addition, exposure to Trikafta enhances the susceptibility ofA. fumigatusbiofilms to the clinically utilized anti-fungal drug caspofungin. These data suggest Trikafta impacts the cell wall of A. fumigatus and suggests the potential for using Trikafta to augment existing anti-fungal therapy.