STAT1 signaling controls cholesterol metabolism in epithelial cells and RSV-induced syncytia formation

Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections, leading to significant morbidity, hospitalizations, and mortality among high-risk populations. Despite the recent advent of vaccines and monoclonal antibodies, options to treat RSV infections are limited. Detailed understanding at the molecular level of virus-host interactions associated with disease severity may aid development of novel intervention strategies. In this study, we examined the role of transcription factor STAT1 in regulating cholesterol metabolism during RSV infection of epithelial-like cells. We demonstrated that CRISPR/Cas9-mediated STAT1 knock-out affected activation of the SREBP-SCAP cholesterol biosynthesis pathway, leading to intracellular cholesterol accumulation and increased RSV-induced syncytia formation. Pharmacological reduction of cholesterol levels blunted RSV-induced syncytia formation and affected the stability of the RSV fusion protein. These findings reveal a STAT1-dependent immune-metabolic pathway that constrains RSV dissemination through syncytia formation, which could be a novel target for intervention strategies.