EBioMedicine · 2026
CFTR modulators partially restore the epithelial interferome in Aspergillus infection to improve clinical outcome.
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Laverty Sarah L, Felton Imogen, Casey Michelle, Hopwood Benjamin, Simmonds Nicholas, Armstrong-James Darius, Shah Anand, Kelleher Peter
Аннотация
BACKGROUND: 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.
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: This study was funded by the Cystic Fibrosis Trust (SRC015).
METHODS: 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.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: This study was funded by the Cystic Fibrosis Trust (SRC015).