By sequencing genes from over a quarter of a million cells across six mammalian species, researchers have shown how genes in the immune response have varied activity between cells and species.

The study, published in Nature, looked in unprecedented detail at the genes that are activated in a cell's initial response to a pathogen invasion - the innate immune response. They measured the activity of thousands of genes in over 250,000 individual cells using single cell genomics technology to chart the evolution of antiviral and antibacterial immunity.

Previous work has shown that many genes in the innate immune response have rapidly evolved in vertebrates. This is thought to be caused by the relentless pressure of attack from pathogens like bacteria and viruses. These include genes that make cytokine and chemokine molecules, which act in a variety of ways - some are inflammatory molecules that alert the body to danger; others restrict a pathogen's ability to multiply and others induce cell death. They represent a successful host strategy to counteract rapidly evolving pathogens.

Using bulk and single-cell transcriptomics in fibroblasts and mononuclear phagocytes from different species, challenged with immune stimuli, authors map the architecture of the innate immune response. Transcriptionally diverging genes, including those that encode cytokines and chemokines, vary across cells and have distinct promoter structures.

Conversely, genes that are involved in the regulation of this response, such as those that encode transcription factors and kinases, are conserved between species and display low cell-to-cell variability in expression. These genes may be under tighter constraints because they are involved in many different functions within cells. But, they are also targeted by viruses. These constrained genes represent an Achilles' heel, used by pathogens to subvert the immune system.

Authors suggest that this expression pattern, which is observed across species and conditions, has evolved as a mechanism for fine-tuned regulation to achieve an effective but balanced response.

The lead author of the research said: "We think that this pattern of activation - where some genes are under tight control, and others have more variable activity - has evolved as a way to fine-tune the immune response. It is effective, but balanced. Genes can evolve to help a cell control an attacker, and the use of those genes can vary between cells, so surrounding tissues are not affected by a massive fall-out."

https://www.sanger.ac.uk/news/view/study-reveals-how-gene-activity-shapes-immunity-across-species

https://www.nature.com/articles/s41586-018-0657-2