Functional diversity of natural human <i>IFNB1</i> variants in innate immunity

Human interferon-β (IFN-β), a type I IFN, is critical for effective innate immunity and is also an approved disease-modifying therapeutic. While genetic variations in several components of the type I IFN system are associated with infectious and immune diseases, consequences of IFNB1 variation remain unexplored. Here, we functionally evaluated 70 naturally occurring rare protein-altering IFNB1 variants detected in humans globally. Twenty-five percent of all protein variants were found to be substantially less active than the common reference IFN-β, a phenotype that for many correlated with retention in the ER and poor secretion, or to compromised interaction with IFNAR1/IFNAR2 cell surface receptors. Notably, three IFNB1 variants, including one found to be homozygous in a single individual, encode IFN-β proteins with enhanced capacity to engage IFNAR1/IFNAR2 and which exhibit greater signaling and antiviral potency than common IFN-β. Our mechanistic survey of natural human IFN-β functional diversity provides a framework to explore both disease associations and the optimization of human IFN-β in next-generation therapeutics.