When viruses meet cystic fibrosis: Insights into host-pathogen dynamics

Cystic fibrosis (CF), an autosomal-recessive genetic disorder, is caused by mutations in the CFTR gene, which encodes for a membrane anion channel expressed on multiple organs, with major impact on the airways. The impaired ion transport leads to thickened mucus secretions, which in turn can cause pancreatic insufficiency, sinusitis, infertility and, particularly, chronic pulmonary infections. While bacterial colonization of the airways has been extensively studied, increasing evidence highlights the significant, yet underappreciated, role of respiratory viruses in exacerbating lung disease in people with CF (pwCF). This review provides a comprehensive overview of the pathogenesis, epidemiology, and clinical impact of key respiratory viruses, including respiratory syncytial virus (RSV), human rhinovirus (HRV), influenza viruses, parainfluenza viruses, coronaviruses, and emerging pathogens such as human bocavirus, as well as relevant non-respiratory viruses, such as Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and hepatitis viruses. Viral infections in pwCF are associated, particularly in pediatric patients, with increased respiratory symptoms, higher hospitalization rate and long-term decline in lung function. Despite a similar incidence of viral infections to non-CF individuals, pwCF often exhibit more severe clinical outcomes, except for SARS-CoV-2 infection, which shows an incidence and severity unexpectedly attenuated in this cohort. Moreover, while CFTR modulators have dramatically improved clinical outcomes in pwCF, their effects on antiviral immunity remain poorly understood and are an area of active investigation. Elucidating virus-host interactions and the impact of CFTR restoration in this context is essential for optimizing preventive and therapeutic strategies against viral infections in CF.