Nature (2018)

The innate immune response is the first line of defense against pathogens. In Nature, Hagai et al. use bulk and single-cell transcriptomics analysis of fibroblasts and bone marrow–derived mononuclear phagocytes (from humans, mice and several other mammals) stimulated with the double-stranded RNA poly(I:C) or lipopolysaccharide, respectively, to map the architecture of the innate immune response. The most divergent genes in both fibroblasts and phagocytes have promoter architectures with high sequence conservation, enrichment for TATA boxes and depletion of CpG islands. Cytokines, chemokines and their receptors diverge more than do chromatin modulators, transcription factor or kinases. Genes that are highly divergent between species are also more variable in expression across individual cells within a species, with only a small subset of responding cells expressing various cytokines. Transcriptionally divergent genes are evolutionarily younger and encode proteins with fewer interactions with other proteins. Viruses target conserved modulators of the immune response.