Next-Generation Interferons: Mapping and Engineering Antiviral Function

Modern medicine has learned to harness adaptive immunity through vaccines, monoclonal antibodies, and engineered T cells. In contrast, the innate immune system-our first and most universal line of defense-remains largely untapped as a therapeutic frontier. Interferons (IFNs) sit at the core of this system, yet we lack a predictive framework linking IFN sequence, timing, and cross-family signaling to biological function. The human genome encodes 22 distinct IFNs with multiple alleles and polymorphisms, but their functional "grammar"-the rules that govern antiviral potency, duration, and inflammatory cost-remains unreadable. The stakes are high. In collaboration with Jean-Laurent Casanova (HHMI, Rockefeller University), we found that autoantibodies neutralizing type I IFNs account for ~15% of critical COVID-19 pneumonia and ~20% of related deaths, while recessive inborn errors of IFN immunity explain ~10% of pediatric COVID-19 hospitalizations and cause severe reactions to live-attenuated vaccines. Defective IFN function-whether due to genetics or autoantibodies-is therefore one of the strongest known risk factors for life-threatening viral disease. Yet we still cannot interpret patient IFN variants or design new IFN therapies that resist antibody blockade while avoiding inflammation. To close this gap, I propose SuperScan, a synthetic-DNA-enabled, arrayed screening platform to decode the IFN sequence-function grammar. Unlike pooled approaches, which lose genotype-phenotype linkage once secreted proteins diffuse, SuperScan preserves spatial separation, enabling precise, time-resolved measurements of antiviral activity, inflammatory signaling, cell viability, and autoantibody susceptibility. Aim 1 will build the first systematic functional atlas of human IFNs and their natural variants. Aim 2 will engineer next-generation IFN-λ3 variants with optimized potency and safety. Aim 3 will map the combinatorial logic of type I and type III IFNs-defining how these cytokines cooperate or antagonize each other to balance protection and inflammation. I am uniquely positioned to lead this effort. During my postdoctoral training with Charles M. Rice (2020 Nobel Laureate, Rockefeller University), I developed genome-scale, arrayed infection assays under authentic viral challenge-the technical and conceptual foundation for SuperScan. This high-risk, high-reward project will deliver the first predictive framework linking IFN sequence and timing to biological function. By redefining type I and III IFNs not as redundant antiviral signals but as parameters of a molecular code that programs the strength, duration, and inflammatory cost of innate immunity, this work establishes a foundation for programmable cytokine engineering. Beyond interferons, SuperScan provides a versatile blueprint for decoding and designing other immune mediators, directly advancing the NIAID mission to prevent and treat infectious and immune-mediated diseases.