Ancient microbes linked to evolution of human immune proteins

When you’re infected with a virus, some of the first weapons your body deploys to fight it are ones our microbial ancestors passed down to us billions of years ago. Two key components of our innate immune system come from a group of microbes called Asgard archaea, according to a new study from the University of Texas at Austin.

Specifically, the proteins viperin and argonaute, two proteins known to play important roles in the immune systems of all complex life—from insects to plants to humans—came from Asgardian archaea. Versions of these defense proteins are also present in bacteria, but the versions in complex life are more closely related to those in Asgardian archaea, according to a new study published in the journal Nature Communications.

This research reinforces the idea that all complex life, called eukaryotes, arose from a symbiotic relationship between Asgard bacteria and archaea.

“This confirms that the Asgards are our microbial ancestors,” said Brett Baker, associate professor of integrative biology and marine sciences and senior author of the study. “It shows that not only did eukaryotes get all these rich structural proteins that we’ve already seen in the Asgards, but now it shows that even some of the defense systems of eukaryotes come from the Asgards.”

Researchers have identified for the first time a broad arsenal of defense systems in archaea that were previously only known in bacteria.

When vipers detect foreign DNA, which could indicate the presence of a dangerous virus, they modify the DNA so that the cell can no longer make copies of it, which stops the virus from spreading. When argonauts detect foreign DNA, they cut it up, which also stops the virus. Additionally, in more complex organisms, argonauts can stop the virus from making proteins in a process called RNA silencing.

“Viral infections are one of the evolutionary pressures we’ve been under since the beginning of life, and it’s essential to always have some form of defense,” says Pedro Leão, now an assistant professor at Radboud University in the Netherlands and a postdoctoral researcher in Baker’s lab. “When bacteria and archaea discovered effective tools, they were passed on and are still part of our first line of defense.”

It’s the shape of a protein that determines how it works. The researchers compared proteins involved in immunity across the tree of life and found many closely related proteins. They then used an AI tool called ColabFold to predict whether those with similar amino acid sequences also had similar three-dimensional shapes (also called structures).

This study showed that variations of the viperin protein likely retained the same structure and function throughout the tree of life. They then created a kind of family tree, or phylogeny, of these sister amino acid sequences and structures that showed evolutionary relationships.

Finally, the researchers took viperins from Asgard archaea genomes, cloned them into bacteria (so that the bacteria would express the proteins), challenged the bacteria with viruses, and showed that the Asgard viperins actually offered some protection to the engineered bacteria. They survived better than bacteria without the immune proteins.

“This research highlights the critical role that cellular defenses must have played early in prokaryotic and eukaryotic life,” said Emily Aguilar-Pine, a former undergraduate researcher who contributed to the project. “It also raises questions about how our modern understanding of eukaryotic immunity can benefit from revealing some of its most ancient origins.”

“It is undeniable at this point that the Asgardian archaea have contributed greatly to the complexity we see in eukaryotes today,” Leão said. “So why wouldn’t they also be involved in the origin of the immune system? We now have strong evidence that this is true.”

Other authors, all from UT, are Mary Little, Kathryn Appler, Daphne Sahaya, Kathryn Currie, Ilya Finkelstein and Valerie De Anda.