A Balance Between Regulatory Constraints And Pathogen Pressure Shapes The Evolution Of Innate Immunity

The immune system is under constant pressure from pathogens to evolve and mount a sufficiently strong response. At the same time, an overresponsive immune system can lead to autoimmunity and tissue damage. How these conflicting demands have shaped human immunity is not well understood. Here, we characterize transcriptional divergence in the innate immune response across primates and rodents using bulk and single-cell transcriptomics, combined with chromatin analysis. We discover that genes that diverge in transcriptional response across species vary in cell-to-cell expression within each species. These divergent genes are evolutionarily younger, experience rapid coding sequence evolution and display a distinct promoter architecture. They have exclusive immune functions, such as cellular defence and inflammation, while pleiotropic genes involved in immunity and other pathways are more conserved. Analysis of viral interactions and mimicry shows that viruses target conserved elements of the innate immune response, suggesting that regulatory constraints imposed on the host are exploited by viruses. Importantly, innate immune genes implicated in autoimmune diseases show high levels of transcriptional divergence but also more interactions with viruses. This reveals a conflict between pathogens and regulatory constraints, which has likely contributed to genetic architectures driving the pathogenesis of immune disorders.