{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T04:04:48Z","timestamp":1775189088589,"version":"3.50.1"},"reference-count":107,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"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>","DOI":"10.3389\/fcimb.2026.1754083","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:52:47Z","timestamp":1774421567000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Host transcriptomic analysis reveals a defective intracellular environment that limits SARS-CoV-2 replication in CFTR-deficient airway epithelium"],"prefix":"10.3389","volume":"16","author":[{"given":"Anna","family":"Lagni","sequence":"first","affiliation":[{"name":"Microbiology Section, Department of Diagnostic and Public Health, University of Verona","place":["Verona, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Lotti","sequence":"additional","affiliation":[{"name":"Microbiology Section, Department of Diagnostic and Public Health, University of Verona","place":["Verona, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo","family":"Cecchetto","sequence":"additional","affiliation":[{"name":"Microbiology Section, Department of Diagnostic and Public Health, University of Verona","place":["Verona, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Tonon","sequence":"additional","affiliation":[{"name":"Unit\u00e0 Operativa Complessa (UOC) Micorbiology, Azienda Ospedaliera Universitaria Integrata (AOUI) Verona","place":["Verona, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erica","family":"Diani","sequence":"additional","affiliation":[{"name":"Microbiology Section, Department of Diagnostic and Public Health, University of Verona","place":["Verona, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asia","family":"Palmisano","sequence":"additional","affiliation":[{"name":"Microbiology Section, Department of Diagnostic and Public Health, University of Verona","place":["Verona, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pier Paolo","family":"Piccaluga","sequence":"additional","affiliation":[{"name":"Biobank of Research, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliera-Universitaria di Bologna Policlinico di S. 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