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

DOI record: { "DOI": "10.3389/fcimb.2026.1754083", "ISSN": [ "2235-2988" ], "URL": "http://dx.doi.org/10.3389/fcimb.2026.1754083", "abstract": "<jats:p>\n 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 change&amp;gt;1 between groups (p&amp;lt;0.05) and significant DEGs were subjected to Gene Ontology and KEGG enrichment analysis (p&amp;lt;0.05). Our results reveal that CFTR deficiency impairs SARS-CoV-2 replication not by altering receptor availability (e.g.,\n <jats:italic>ACE2, TMPRSS2</jats:italic>\n ), 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.\n </jats:p>", "alternative-id": [ "10.3389/fcimb.2026.1754083" ], "article-number": "1754083", "author": [ { "affiliation": [ { "name": "Microbiology Section, Department of Diagnostic and Public Health, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Lagni", "given": "Anna", "sequence": "first" }, { "affiliation": [ { "name": "Microbiology Section, Department of Diagnostic and Public Health, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Lotti", "given": "Virginia", "sequence": "additional" }, { "affiliation": [ { "name": "Microbiology Section, Department of Diagnostic and Public Health, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Cecchetto", "given": "Riccardo", "sequence": "additional" }, { "affiliation": [ { "name": "Unità Operativa Complessa (UOC) Micorbiology, Azienda Ospedaliera Universitaria Integrata (AOUI) Verona", "place": [ "Verona, Italy" ] } ], "family": "Tonon", "given": "Emil", "sequence": "additional" }, { "affiliation": [ { "name": "Microbiology Section, Department of Diagnostic and Public Health, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Diani", "given": "Erica", "sequence": "additional" }, { "affiliation": [ { "name": "Microbiology Section, Department of Diagnostic and Public Health, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Palmisano", "given": "Asia", "sequence": "additional" }, { "affiliation": [ { "name": "Biobank of Research, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera-Universitaria di Bologna Policlinico di S. Orsola", "place": [ "Bologna, Italy" ] }, { "name": "Department of Medical and Surgical Sciences, Bologna University School of Medicine", "place": [ "Bologna, Italy" ] } ], "family": "Piccaluga", "given": "Pier Paolo", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biotechnology, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Calgaro", "given": "Matteo", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Biotechnology, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Vitulo", "given": "Nicola", "sequence": "additional" }, { "affiliation": [ { "name": "General Pathology Section, Department of Medicine, University of Verona", "place": [ "Verona, Italy" ] } ], "family": "Sorio", "given": "Claudio", "sequence": "additional" }, { "affiliation": [ { "name": "Microbiology Section, Department of Diagnostic and Public Health, University of Verona", "place": [ "Verona, Italy" ] }, { "name": "Unità Operativa Complessa (UOC) Micorbiology, Azienda Ospedaliera Universitaria Integrata (AOUI) Verona", "place": [ "Verona, Italy" ] } ], "family": "Gibellini", "given": "Davide", "sequence": "additional" } ], "container-title": "Frontiers in Cellular and Infection Microbiology", "container-title-short": "Front. 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