Differential interferon-α immune signatures prevent SARS-CoV-2 infection

Type 1 interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control and immune-mediated pathology and have been successfully employed for the treatment of viral diseases. In humans, there are twelve IFN-alpha (α) subtypes, which activate downstream signalling cascades and result in a distinct pattern of immune responses and differential antiviral responses. In this project, we analysed the antiviral activity of IFNα subtypes towards SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Pre-treatment of primary human airway epithelial cells (hAEC) cells with different human IFN-α subtypes demonstrated distinct antiviral activities against SARS-CoV-2. We identified IFNα5 as one of the strongest antiviral acting IFNs against SARS-CoV-2 infection in this study. Dose-dependency studies displayed an additive effect when co-administered with the broad antiviral drug remdesivir in cell culture. Bulk transcriptomics of pre-treated hAEC revealed differentially expressed gene signatures, with IFNα subtype-specific distinct, intersecting and common genes. Proteomic analysis confirmed the expression of distinct interferon effectors for the subset of highly antiviral IFNα5. Therefore, our data elucidate molecular antiviral host responses upon treatment with type I IFNs on several levels, knowledge which could aid in the development of novel therapeutic approaches. Primary human airway epithelial cells (hAEC) of four different donors were pre-treated with IFNalpha subtypes. Sixteen hours port stimulaiton, cells were lysed and total RNA was sequenced. In addition, untreated cells were infected with SARS-CoV-2