# CFTR modulators partially restore the epithelial interferome in Aspergillus infection to improve clinical outcome

## TL;DR

CFTR modulators help improve lung disease outcomes in cystic fibrosis patients infected with Aspergillus by partially restoring immune responses.

## Contribution

This study shows that CFTR modulators partially restore the epithelial interferon response to Aspergillus in cystic fibrosis.

## Key findings

- CFTR modulator therapy reduced Aspergillus biomarkers and use of corticosteroids and antifungal drugs.
- ETI therapy partially restored type I/III interferon gene expression in CF bronchial epithelial cells.
- Exogenous IFNλ1 improved antifungal killing in CF neutrophils without increasing harmful byproducts.

## Abstract

The impact of CFTR modulator therapy on host immunity and outcomes in people with Cystic Fibrosis (CF)-related Aspergillus lung disease is poorly defined. We aimed to characterise fungal-relevant clinical outcomes post-CFTR modulators and assess effects on the Aspergillus-dependent Type I/III interferome.

Biomarkers of Aspergillus-related lung disease (Aspergillus-specific IgE/IgG), anti-fungal and corticosteroid therapy were analysed in a retrospective cohort of people with CF pre and post Elexacaftor/Tezacaftor/Ivacaftor (ETI) modulator therapy. Homozygous F508del (CF) and CFTR TALEN-corrected bronchial epithelial cells (BECs) were challenged with Aspergillus conidia and hyphae in the presence or absence of ETI CFTR modulator therapy with bulk RNA transcriptomics and RT-PCR used to analyse Type I/III interferon genes. Effects of exogenous type I and III interferons on CF-neutrophil antifungal effector function was further characterised.

CFTR modulator (ETI) therapy was associated with a significant reduction in Aspergillus biomarkers alongside use of corticosteroid and anti-fungal therapy. In vitro Aspergillus stimulation enriched the Type I/III interferome in CFTR-corrected BECs compared to CF BECs, with ETI therapy partially restoring type I/III interferon gene expression in CF BECs. Administration of exogenous IFNλ1 increased anti-fungal killing in CF neutrophils without increased reactive-oxygen species or neutrophil extracellular trap production.

CFTR modulators have led to improved clinical outcomes in CF related Aspergillus-related lung disease potentially due to partial restoration of the host antifungal epithelial type I/III interferon response. Exogenous IFNλ1 further improved antifungal killing capacity of CF-neutrophils presenting a plausible future therapeutic strategy.

This study was funded by the 10.13039/501100000292Cystic Fibrosis Trust (SRC015).