By sequencing genes from across six mammalian species, a team of researchers show how immune-regulating genes have varied activity between cells and species. The study, published today in Nature, looks in unprecedented detail at the genes that are activated in a cell's initial response to a pathogen invasion. The team 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, perhaps due to the relentless pressure of attack from rapidly evolving pathogens. 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.
While these rapidly evolving genes have highly variable activity in different cells within an individual’s tissue, the team found that immune-regulating genes that are conserved between species are more consistently activated across cells within a tissue. 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” that is used by pathogens to subvert the immune system.
"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,” says lead author Tzachi Hagai of the Wellcome Sanger Institute. “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."
Senior author Sarah Teichmann, also of the Wellcome Sanger Institute, adds that "the power of DNA sequencing at the resolution of single cells means this kind of study is now possible. There are an estimated 37 trillion cells in the human body, each with the same genetic code. But individual cells behave differently; they use that genetic code in a different way. By studying individual cells we can understand these fundamental building blocks of life and how they work together—including how they resist pathogens."