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.
