25 October, Hinxton – By sequencing genes from over a quarter of a million cells across six mammalian species (including humans, macaques, mice and rats), researchers at EMBL’s European Bioinformatics Institute (EMBL-EBI), the Wellcome Sanger Institute, and collaborators, have shown how genes involved in the immune response have varied activity between cells and species. This information will help explain why some mammals are more or less susceptible to some pathogens than other mammals.

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. Researchers measured the activity of thousands of genes in more than 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 evolved rapidly in vertebrates. This is thought to be caused by the relentless pressure of attack from pathogens like bacteria and viruses. These genes include those that encode 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.

The researchers showed that these genes, which have evolved rapidly across species, also have highly variable activity in different cells within the same tissue.

Defence and preservation

“We think 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,” explains Tzachi Hagai, a postdoctoral fellow at EMBL-EBI and 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.”

Researchers also found that genes which are conserved between species, and which regulate the immune response, 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, used by pathogens to subvert the immune system.

What next?

“This work included both experimental elements and computational analysis. Much of the computation was performed at EMBL-EBI, where the data is being stored,” adds Hagai. “We will be utilising the data in future studies – to look at the details of the differences between species and cells in response to pathogens. This will help explain why we are more susceptible to some pathogens while other, closely related, mammals can resist them.”

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