What question did this study set out to answer?

This research aims to understand how CFTR deficiency affects SARS-CoV-2 replication in bronchial epithelial cells.

March 29, 2026SHILAP Revista de lepidopterología0 citationsOpen Access

Host transcriptomic analysis reveals a defective intracellular environment that limits SARS-CoV-2 replication in CFTR-deficient airway epithelium

ALAnna LagniUniversity of Verona VLV. LottiUniversity of Verona RCRiccardo CecchettoUniversity of Verona

Key Points

This research aims to understand how CFTR deficiency affects SARS-CoV-2 replication in bronchial epithelial cells.
Performed transcriptomic profiling of SARS-CoV-2-infected bronchial epithelial cells with wild-type or mutated CFTR.
Conducted RNA sequencing at multiple time points post-infection.
Applied Gene Ontology and KEGG enrichment analysis to identify significant differentially expressed genes.
CFTR-deficient cells exhibit lower SARS-CoV-2 replication compared to wild-type cells.
Key antiviral and inflammatory responses are not activated in CF cells.
Defective pH regulation and impaired vesicle acidification limit viral assembly.

Abstract

Cystic fibrosis (CF) is characterized by chronic airway inflammation, yet clinical observations have revealed more favorable COVID-19 outcomes than originally predicted. Several studies demonstrated a significant decrease of SARS-CoV-2 replication in CF-mutated bronchial cells suggesting that CFTR dysfunction may interfere with viral replication, though the underlying mechanisms remain unclear. To elucidate these mechanisms we performed transcriptomic profiling of SARS-CoV-2-infected bronchial epithelial cells with wild-type (WT) or mutated CFTR, using both immortalized and primary airway models. RNA-seq was performed on WT and CF cellular models before and at 24, 48, and 72-hours post-infection. The differentially expressed genes (DEGs) were defined as genes with a log2 fold change1 between groups (p0.05) and significant DEGs were subjected to Gene Ontology and KEGG enrichment analysis (p0.05). Our results reveal that CFTR deficiency impairs SARS-CoV-2 replication not by altering receptor availability (e.g., ACE2, TMPRSS2 ), but through widespread intracellular remodeling defects. CF cells failed to activate key antiviral and inflammatory responses, including interferon signaling, AP-1 transcriptional complex, and IL-6-mediated pathways. Furthermore, they exhibited defective unfolded protein response, altered calcium signaling, and disrupted ER-mitochondrial communication. Crucially, pH dysregulation and impaired expression of V-ATPase subunits and autophagy-related genes hindered vesicle acidification, double-membrane vesicle formation, and viral assembly. These intrinsic alterations also blunted virus-induced senescence programs. Collectively, our findings indicate that CF cellular environment is intrinsically unfavorable to SARS-CoV-2, limiting its replication and propagation. This study provides a mechanistic basis for the reduced viral burden observed in CF and highlights intracellular pH regulation and organelle homeostasis as potential therapeutic targets against SARS-CoV-2 infection.

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