The Cystic Fibrosis treatment, Trikafta, affects growth, viability, and cell wall of Aspergillus fumigatus biofilms

Jones, J. T.; Morelli, K. A.; Vesely, E. M.; Puerner, C.; Pavuluri, C.; Ross, B. S.; Rhijn, N. v.; Bromley, M. J.; Cramer, R. A.

doi:10.1101/2023.06.20.545692

bioRxiv · 10.1101/2023.06.20.545692

The Cystic Fibrosis treatment, Trikafta, affects growth, viability, and cell wall of Aspergillus fumigatus biofilms

Jones, J. T.·Morelli, K. A.·Vesely, E. M.·Puerner, C.·Pavuluri, C.·Ross, B. S.·Rhijn, N. v.·Bromley, M. J.·Cramer, R. A.

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Abstract

People 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 affects A. fumigatus growth and biology. While Trikafta did not impact the viability of A. fumigatus conidia, treatment of A. fumigatus biofilms 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 gene sakA. 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-relevant A. fumigatus biology 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 of A. fumigatus, termed biofilms. When exposed to Trikafta A. fumigatus biofilms lose their viability. In addition, exposure to Trikafta enhances the susceptibility of A. fumigatus biofilms 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.

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Jones, J. T., Morelli, K. A., Vesely, E. M., Puerner, C., Pavuluri, C., Ross, B. S., Rhijn, N. v., Bromley, M. J., Cramer, R. A.. 2023-06-21. The Cystic Fibrosis treatment, Trikafta, affects growth, viability, and cell wall of Aspergillus fumigatus biofilms. https://doi.org/10.1101/2023.06.20.545692

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