What if bacteria held the keys to a part of our own immunity? For several years, some scientists have been exploring unexpected links between human proteins involved in the body's defense and certain bacterial immune mechanisms. This is the case for a team of scientists from the Institut Curie, the Institut Pasteur, and Inserm who have just identified a protein in humans with a previously unknown role: SIRal, derived from a so-called "ancestral immune" bacterial domain.
Pixabay illustration image
Published in
Science on July 24, 2025, their work reveals a principle of biological conservation that opens new avenues in immunotherapy by proposing novel therapeutic targets originating from bacterial evolution itself.
For a long time, scientists believed they had identified the main pathways of innate immunity in humans, which constitutes the body's first line of defense. Indeed, innate immunity allows for the detection of certain pathogens and triggers a rapid response. Yet today,
ancestral immunity, a rapidly expanding field of research, is challenging this dogma.
By exploring the evolutionary links between bacterial and human proteins, researchers are realizing that a significant number of proteins involved in innate immunity in humans derive from those present in bacteria. These proteins are not only structurally conserved: their immune role is also preserved, sometimes over billions of years.
In bacteria, the SIR2 (silent information regulator 2) protein domain plays a key role in defense systems against phages, viruses that specifically infect bacteria. When a phage enters a bacterium, SIR2 triggers the degradation of a molecule essential for cellular metabolism and causes the death of the infected cell, thereby protecting the rest of the colony.
Phylogenetic tree constructed from bacterial (blue) and eukaryotic (green) SIR2 domain proteins. The proteins are divided into two subfamilies, one of which, the sirims, contains the immune SIR2 proteins, including SIRal.
By reconstructing the evolutionary history of genes through phylogeny[1], a team led by Dr. Enzo Poirier, a researcher at Inserm, team leader at the Institut Curie in the Immunity and Cancer unit (Institut Curie, Inserm) and Dr. Aude Bernheim, head of the Microbial Molecular Diversity unit at the Institut Pasteur, identified a human homolog of the SIR2 domain, named SIRal, and demonstrated its role in innate immunity as well as its ability to degrade NAD, a molecule essential for cellular metabolism and energy production.
The discovery of SIRal's biological role is all the more interesting as it concerns not just a single isolated protein but a diverse family of proteins found in 19% of the analyzed eukaryotic genomes, distributed across five major lineages. These results confirm that immune mechanisms of bacterial origin are not only present but widely conserved within living organisms, with potential implications for all eukaryotes, including humans.
In addition to the phylogenetic approach, Dr. Delphine Bonhomme (Poirier team), Hugo Vaysset (Bernheim team) and their colleagues demonstrated that SIRal acts as a central regulator of the TLR (
Toll-like receptors) pathway, a family of receptors capable of detecting typical signals from pathogens.
Thus, this TLR pathway regulated by SIRal facilitates the expression of pro-inflammatory genes and triggers the immune reaction. They showed that without SIRal, the inflammatory response is severely impaired, whether facing a bacterial or viral infection.
"
With SIRal, we show that elements inherited from bacteria can play a central role in eukaryotic immune mechanisms, particularly human ones. But more broadly, ancestral immunity gives us access to an unsuspected reservoir of immune mechanisms," emphasizes Enzo Poirier, researcher at Inserm and team leader at the Institut Curie.
"This discovery illustrates how evolution reuses old building blocks to create new functions: mechanisms born in bacteria billions of years ago still shape our immunity today," specifies Aude Bernheim, head of the Microbial Molecular Diversity unit at the Institut Pasteur.
Beyond evolutionary biology, the implications of the SIRal discovery are clinical. Indeed, many autoimmune pathologies depend partly on the activation of TLR receptors. SIRal therefore represents a novel therapeutic target, paving the way for a new kind of immunotherapy.
Note:
[1] Phylogeny refers to the study of evolutionary links between species, aiming to reconstruct their kinship relationships from a common ancestor.