Mechanistic insights into how CFTR dysfunction affects the host response to SARS-CoV-2 in bronchial epithelial models

Cystic fibrosis (CF) is a severe, inherited autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride and bicarbonate channel critical for epithelial homeostasis. Defective CFTR function impairs ion transport, alters mucus properties, and promotes chronic airway inflammation. Respiratory viruses are clinically significant in CF because they exacerbate lung disease; however, epidemiological data from the COVID-19 pandemic revealed that individuals with CF experienced a milder disease course and a lower than-expected incidence of SARS-CoV-2 infection than initially expected. These findings led us to study, at a mechanistic level, how CFTR dysfunction shapes host-virus interactions. In this thesis, I investigated the role of CFTR in the context of SARS-CoV-2 infection, using both airway epithelial cell lines and primary bronchial epithelial models. First, pharmacological inhibition of CFTR was tested to evaluate its impact on SARS-CoV-2 replication in vitro. Next, transcriptomic analyses were performed to compare the host response to SARS-CoV-2 between CFTR-deficient and wild-type cells, with a particular focus on pathways related to intracellular remodeling, acidification, autophagy, and senescence. The results revealed that CFTR inhibition reduced viral replication in vitro, suggesting that CFTR activity may facilitate the SARS-CoV-2 life cycle. Transcriptomic profiling further showed that CFTR-deficient cells exhibited a distinct host response characterized by defective, intracellular trafficking and altered vesicular pathways, which may limit viral replication. Genes involved in inflammatory response, autophagy and senescence were also differentially regulated, providing new insights into the interplay between CFTR dysfunction and host antiviral defense. Overall, this work identifies CFTR as a host factor contributing to SARS-CoV-2 replication and highlights how its deficiency creates an intracellular environment that restricts viral propagation. These findings improve our understanding of viral infections in CF and may open new perspectives for therapeutic interventions targeting host pathways.