Understanding immune signaling in bacteria and beyondcore
ImmuneTIRs · Horizon Europe grant · 2027-01-01–2031-12-31
EC contribution
Total cost
Beneficiaries
About the data
Source: CORDIS (official EU open data), Horizon Europe. Framework HORIZON · call ERC-2025-ADG · scheme HORIZON-ERC · topic ERC-2025-ADG. CORDIS record →
Objective
In recent years, systematic genome mining of bacterial “defense islands” revealed hundreds of defense systems that protect bacteria from phages, revolutionizing our view of microbial immunity. Our lab has played a central role in this revolution: we discovered numerous new defense systems and showed that human immune pathways such as cGAS–STING and pyroptosis evolved from bacterial defenses. These insights established microbes as model organisms for uncovering new immune pathways.The focus of the current project stems from our discovery that Toll/Interleukin-1 receptor (TIR) domains in bacteria defend against phages by producing small-molecule immune signals. These findings transformed the view of TIRs, previously thought to act only as protein scaffolds in animal immunity, and inspired the discovery that TIR proteins in plants also generate small-molecule signals central to plant immunity. Our studies described three types of bacterial TIR signaling systems, each producing a distinct molecule (Leavitt Nature 2022; Sabonis Nature 2025; Rousset Science 2025). Our preliminary data now reveal numerous additional TIR systems, and indicate that catalytically active TIRs are widespread in animals and other eukaryotes, pointing to a vast diversity of immune signals and pathways waiting to be discovered.This project will systematically chart the universe of TIR-based immune signaling. We will mine massive genomic and metagenomic data to discover and study new TIR-dependent systems in bacteria (Aim I), apply large-scale metabolomics and biochemical analyses to define their signaling molecules and effectors (Aim II), and extend this framework across animals, plants, and other eukaryotes (Aim III). By mapping the full breadth of TIR signaling, we aim to uncover fundamental rules of immune signaling, reveal evolutionary links between microbial and eukaryotic immunity, and expose new signaling pathways that shape innate immunity across the tree of life.
Beneficiaries (1)
| Organisation | Country | Role | EC contribution | SME |
|---|---|---|---|---|
| WEIZMANN INSTITUTE OF SCIENCE | IL | coordinator | €2,500,000 |
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