Genetic and chemical correction of cystic fibrosis reduces airway susceptibility to SARS-CoV-2

The airway epithelium, a primary target for viral infection, plays a critical role in disease response-particularly in individuals with preexisting airway conditions such as cystic fibrosis (CF). At the onset of the SARS-CoV-2 pandemic, individuals with CF were expected to have severe outcomes based on earlier viral outbreaks; however, those on effective CF transmembrane conductance regulator (CFTR) modulators showed milder disease. Patients with CF on the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) combination therapy showed attenuated viral infection and reduced airway epithelial damage. To investigate how this is accomplished, we used an induced pluripotent stem cells (iPSC)-derived airway epithelium model of CF and syngeneic CFTR-corrected cells to examine responses to SARS-CoV-2 infection. CF iPSC-airways were significantly more susceptible to viral infection and epithelial injury compared with their corrected counterparts, despite comparable expression of viral entry factors. Strikingly, pretreatment with ETI conferred significant protection in CFTR-corrected and non-CF, wild-type (WT) airway epithelia, as well as in iPSC-derived and primary epithelia. Single-cell RNA sequencing analysis confirmed a heightened infection and proinflammatory response in CF iPSC-airways, whereas ETI treatment significantly reduced these responses in both CF and CFTR-corrected iPSC-airways. Mechanistically, ETI treatment led to increased type I interferon signaling and induction of antiviral genes, whereas expression of many other proinflammatory genes was suppressed in both CF and non-CF iPSC-airways. These results underscore the therapeutic promise of CFTR-modulators such as ETI in mitigating SARS-CoV-2 infection and inflammation, not only in CF airways but also in non-CF airways, highlighting the broad applicability of CFTR-modulators as a therapeutic strategy in viral pneumonia and inflammatory lung disease.<b>NEW & NOTEWORTHY</b> Using rigorously controlled iPSC-derived airway models, the study shows that CFTR-deficient cells are more vulnerable to SARS-CoV-2 and display stronger inflammation than syngeneic CFTR-corrected controls. The CFTR modulator ETI reduces viral injury and boosts antiviral pathways in both CF and non-CF cells. Even at baseline, CFTR modulation enhances antiviral responses and lowers inflammation. Overall, the findings reveal a broad protective antiviral effect of CFTR modulators and highlight their therapeutic promise in inflammatory lung disease.