Single-cell atlas of transcript usage remodelling in antiviral immune responses across human populations

Abstract Humans exhibit substantial interindividual variation in their immune responses to infection, yet the contribution of transcript usage —the relative abundance of gene isoforms— to this variation remains poorly understood. Here, we generate the first single-cell atlas of transcript usage variation during early responses to influenza A virus and SARS-CoV-2 across 160 individuals of African and European ancestry. We show that viral stimulation induces widespread remodelling of transcript usage across all major immune lineages, with changes that are largely lineage-restricted and frequently undetected at the gene expression level. We further find that ancestry-associated effects on transcript usage are predominantly cell type-specific and contribute to population differences in antiviral responses. In addition, the genetic regulation of transcript usage during stimulation differs between influenza A and SARS-CoV-2, pointing to virus-dependent regulatory architectures. Together, our findings establish transcript usage as a dynamic regulatory layer shaping responses to viral infection across immune cell types and human populations, providing new insights into the molecular basis of variation in human antiviral immunity. Competing Interest Statement The authors have declared no competing interest.