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 pre-existing airway conditions such as cystic fibrosis (CF). At the onset of the SARS-CoV-2 pandemic, CF individuals were expected to have severe outcomes based on prior viral outbreaks; however, those on effective CFTR modulators showed milder disease. CF patients 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 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 to their corrected counterparts, despite comparable expression of viral entry factors. Strikingly, pretreatment with ETI conferred significant protection in CFTR-corrected and non-CF, wildtype (WT) airway epithelia, as well as in iPSC-derived and primary epithelia. Single-cell RNA sequencing analysis confirmed a heightened infection and pro-inflammatory response in CF iPSC-airways, while 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, while expression of many other pro-inflammatory genes were suppressed in both CF and non-CF iPSC-airways. These results underscore the therapeutic promise of CFTR-modulators like 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.