Aude BernheimIn a new #preprint we report that recently discovered anti-phages systems (Mokosh, Eleos, Lamassu…) have eukaryotic homologs.
We harnessed this conservation to discover novel defense mechanisms in humans.
Recent data documented that immune pathways like viperins, cGAS and gasdermins, are shared across domains of life. Bacterial anti-phage systems might thus have been the origin of key immune mechanisms in eukaryotes.
See great perspective https://www.nature.com/articles/s41577-022-00705-4
Prokaryote-eukaryote immune conservations were flagged when novel prokaryotic defense systems were discovered. But, could we do it the other way around? Could we start from the prokaryotic systems and find conservations in eukaryotes?
Bacterial origins of human cell-autonomous innate immune mechanisms - Nature Reviews Immunology
The cell-autonomous innate immune system has long been considered an evolutionary innovation of metazoans; however, recent evidence challenges this dogma. This Perspective describes the components of antiviral immunity that are conserved from bacteria to humans, and presents potential evolutionary scenarios to explain the observed conservation.
When we started thinking about this, we hypothesized that:
1) additional antiviral mechanisms might be shared across domains of life
2) novel eukaryotic immune components could be identified by homology with prokaryotic defense systems.
How could we test for that 🤔 ?
We harnessed DefenseFinder, a pipeline that we developed to detect prokaryotic anti-phage systems in bacterial genomes. We decided to run DefenseFinder not on prokaryotic but on eukaryotic genomes !
https://www.nature.com/articles/s41467-022-30269-9
Systematic and quantitative view of the antiviral arsenal of prokaryotes - Nature Communications
Bacteria and archaea have developed multiple antiviral mechanisms. Here, Tesson et al. present a tool that automatically detects known antiviral systems in prokaryotic genomes, and show that variations in antiviral strategies correlate with genome size, viral threat, and lifestyle traits.
And… we found thousands of hits 🤯.
But are these eukaryotic homologs involved in immunity ?
To tackle this, we focused our analysis on humans, where immunity has been deeply studied and launched a great collaboration with Enzo Poirier.
A key pathway involved in protecting the animal germline is the piRNA pathway. It relies on 2 proteins, MOV10L1 and PLD6, which interact together. We found that they share domains with 2 antiphage proteins, Mokosh A & B, that work hand-in-hand in bacteria to counteract infection.
So yes some of these homologs are involved in immunity!
So yes some of these homologs are involved in immunity!
Then came the 🔥 question: could we leverage this method to discover novel antiviral factors in humans?
The answer is yes. We identified a family of ISGs, GIMAPs, resembling components of the Eleos system, and showed that they’re active against Herpes and Sindbis virus!