The type I and type III interferon response in cystic fibrosis Aspergillus fumigatus related lung disease

Abstract

Af is an airborne fungus that healthy human lungs clear daily. Af infection in CF leads to more hospitalizations and intravenous antibiotics, contributing to lung function decline. Recent research highlights type I and III IFNs as crucial for fungal immunity. While these IFNs regulate antifungal neutrophil responses in mice, their role in humans remains unexplored, particularly in CF lungs, where IFN levels are downregulated during bacterial and viral infections.

This study investigated Af infection response with and without CFTR modulators in CF and CF-corrected human BECs. Cells were infected with the Af strain CEA10 as HK conidia or fixed hyphae. Bulk RNA sequencing showed significantly upregulated ISGs in CF-corrected BECs compared to CF BECs post-Af infection. GSEA indicated enriched TRAF6-mediated IRF7 activation in Af-infected CF-corrected BECs, but not in CF BECs. Monolayer and ALI cultures showed significantly reduced IFNβ and IFNλ1 expression in CF BECs compared to CF corrected BECs post-infection. However, no difference was observed in PBMCs from CF patients and healthy donors post-Af infection.

The impact of CFTR modulators (tezacaftor, ivacaftor, and elexacaftor) on the type I and III IFN responses in CF BECs was assessed. Modulator treatment partially restored IFNβ and IFNλ1 expression and significantly upregulated ISGs at 12 hours post-HK conidia infection but not post-hyphae infection. Modulator treatment significantly downregulated NLRC3, a gene inhibiting type I and III IFN signaling through TRAF6, STING and TBK1.

Neutrophils, essential for controlling fungal infections, from healthy donors and CF patients were treated with exogenous IFNβ and IFNλ1. The addition of IFNλ1 (10ng/ml) enhanced the fungicidal capacity of CF neutrophils without increasing NET or ROS.

This study reveals a novel downregulation of type I and III IFN expression in CF BECs after Af infection, a defect partially rescued by CFTR modulators. Exogenous IFNλ1 showed promising antifungal and immunoregulatory effects.