Scientists Find Immune Signal in Human Cells Has Ancient Pedigree

Human cells in distress — either because they’re infected by a virus or have become cancerous — have a formidable army of defenders at their disposal: white blood cells and other agents of the immune system that can come to the rescue.

Bacterial cells aren’t as fortunate. Living in colonies of their own kind, they don’t have the luxury of summoning outside help. Instead, they practice self-sacrifice as a form of communal self-defense.

In a new study, scientists at Dana-Farber have found that a piece of anti-viral machinery thought to exist only in animals operates in bacteria as well. The discovery indicates that far from being a recent evolutionary arrival, the structure originated much further back, at a time when single-celled creatures were the dominant form of life on earth. Moreover, it illustrates how a defense mechanism used by bacteria can be adopted by complex, multi-organed creatures to alert their much more sophisticated and versatile immune systems to infection and cancer.

“We’ve shown that an aspect of immune signaling that had been thought to be reserved to animal cells in fact has a much longer evolutionary history,” says Dana-Farber’s Brianna Lowey, who led the study with Philip Kranzusch, PhD.

Infection sensors

The discovery of an unexpected bacterial inheritance in human cells began with research into an enzyme called cGAS and similar proteins that sense viral infections and cancerous growth. Once activated, these proteins make a small molecule, called a second messenger, that sparks a protein pathway that signals the immune system. In humans, the signal turns on interferon, a substance that marshals an immune system attack on the diseased cell.

The second messenger is held together by two types of bonds: on one side is a “canonical 3’–5’” bond (canonical meaning “typical” or “common”); on the other is a non-canonical 2’–5′ bond.

As their name suggests, canonical 3’–5′  bonds are ubiquitous in biology; they’re found in every life form. Non-canonical 2’–5′ bonds, on the other hand, are extremely rare: the one in the second messenger made by cGAS in animal cells was one of the only ones scientists knew of. For all its rarity, the 2’–5′ bond has a “signal” advantage: It delivers an especially strong signal to activate the immune system — far stronger than the 3’–5′  bond does.

Lowey and her colleagues were studying cGAS signaling in bacteria as a proxy for cGAS signaling in human cells.

“There are a lot of proteins in human cells that are similar to cGAS, but we don’t understand what their role is,” Lowey explains. “Bacteria offers a useful model for studying them: it’s easier to work with and has a much greater diversity of cGAS-like proteins, which helps us get a better handle on what their role is.”

In studying bacteria, the researchers discovered a family of bacteria proteins that respond to signals delivered by molecules with 2’–5′ bonds and protect the cells from viral infection. The inescapable conclusion was that 2’–5′ bonds, thought to be exclusive to animal cells, are an inheritance from a much, much earlier form of life: bacteria.

Diverging routes

Despite this commonality, the defense against viral infection operates far differently in bacteria than in human cells.

“In both cases, the process starts when a virus activates cGAS, which makes the second messenger. But from there, the pathways diverge,” Lowey explains. “In humans, the process results in interferon production, which switches on the cellular immune system — T cells and other cells that attack the invader. But in bacteria, the system just causes infected cells to die.”

Scientists believe that bacteria cells take a more direct route because, lacking an outside rescue squad, self-sacrifice is the most effective way prevent the spread of the virus to their neighbors. 

The ability of advanced life forms to repurpose an ancient structure to their own needs speaks to the creative continuity of nature. A political analogue might be the Electoral College, an 18^th century invention that still fulfills its original purpose, but in a much different way than its creators envisioned.

Intriguingly, the family of bacterial proteins identified by Lowey and her colleagues are related to those of the CRISPR immune system, by which bacteria defend themselves against viruses by cutting up their DNA.

Researchers expect the newly identified proteins will help them better understand the signaling systems within cells.

“We may be able to use them as tools to measure the presence of second messengers, which has been difficult to assess in the past,” Lowey remarks.