The plot thickens! Exciting new discoveries in the NAD⁺ centric battlefield between bacteria and phages. Congrats, Ilya!
04.02.2026 09:51
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The plot thickens! Exciting new discoveries in the NAD⁺ centric battlefield between bacteria and phages. Congrats, Ilya!
Thank you Jens!
A massive expansion of Thoeris defense systems !
Congrats @erezyirmiya.bsky.social and @soreklab.bsky.social
New Thoeris systems and new bacterial TIRs, this time also producing plant and human immune signals 2'cADPR and cADPR!!! Congratulations to @erezyirmiya.bsky.social and Azita Leavitt! It was a pleasure to be involved in this project.
New Thoeris systems reveal a deep connection between bacterial TIR-produced immune signals to plant and human immunity🦠🌱🧍♀️
It was a great honor to contribute to this project! Congratulations to @erezyirmiya.bsky.social and Azita Leavitt!!🎉🥂
Preprint: Systematic discovery of TIR-based immune signaling systems in bacteria
Conservation of TIR-derived signals accross the tree of life! We found bacterial TIR immune systems that signal via canonical cADPR (like in humans) and 2'cADPR (a plant immune signal).
Documented 11 Thoeris types
Incredible to learn how far-reaching and diverse Thoeris really is! TIRs play key roles across kingdoms, and this work beautifully highlights their bacterial origins.
Congrats @erezyirmiya.bsky.social & Azita! 👏🌟
Thoeris - the gift that keeps on giving 🦠🎁! Congrats Erez, Azita et al.!
And you started it all!
Thank you Sadie!
Huge thanks to co-first author Azita Leavitt - as always, it was so fun and fruitful to work together! Special thanks also to @bhurieva.bsky.social, Alla H. Falkovich, @nbechon.bsky.social, @francoisrousset.bsky.social, @ostermanilya.bsky.social, and @soreklab.bsky.social !
Our work expands the landscape of TIR immune signaling in microbes and reveals unexpected connections with plant and animal immunity. Many Thoeris effectors and signals remain uncharacterized, and uncovering them could once again reshape our understanding of immunity across life🛡️🦠🌱🧍♀️
We found that Thoeris immunity is far more common than previously thought. Thoeris systems appear in ~8% of microbial genomes, about twice what was previously estimated! We also found that ~20% of microbes encode at least one signaling system: Thoeris, CBASS, or Pycsar.
Type VII Thoeris uses a SLATT-domain effector (ThsH), likely forming membrane-breaching oligomers upon cADPR binding, while type VIII encodes a CMP-hydrolase effector (ThsI) predicted to disrupt nucleotide pools to abort phage infection.
Two Thoeris types (types VII and VIII) use canonical cADPR as their immune signal, a molecule well known in human immunity but not previously seen in bacteria. These cADPR-based systems are widespread, revealing a surprising evolutionary link to human immune signaling.
Adding 2′cADPR to cells expressing type VI systems triggered effector-mediated toxicity, and phages engineered to express 2′cADPR-sequestering sponge proteins overcame defense, confirming the signal’s identity!
Most new Thoeris systems did not produce any known Thoeris signals. LC-MS revealed that TIR proteins from type VI Thoeris synthesize 2′cADPR upon phage infection, the same signal broadly used by plant immune TIRs, to activate their cognate effector ThsG.
Structural modeling shows that ThsF forms a membrane-spanning homo-heptamer with positively charged pockets that likely bind 3′cADPR, leading to membrane disruption.
Type V Thoeris detects phage infection and produces the immune signal 3′cADPR (the same signal used by type I). This molecule activates the DUF2270 effector ThsF, whose toxicity is triggered specifically by 3′cADPR and not by related cADPR isomers.
To identify the immune signals of the systems, we expressed each TIR alone, infected with phage, and collected lysates to capture the TIR-derived molecules. We then characterized these signals using LC-MS and in vitro assays that test activation of signal-specific effectors.
We experimentally tested and validated Thoeris operons, expanding Thoeris immunity from four to eleven types (I–XI)!
We found Thoeris effectors ranging from DNases and RNases to phospholipases, ion channels, transmembrane proteins, and many DUFs! Several of these also appear as cell-killing effectors in other defense systems, strongly supporting their roles as new Thoeris effectors.
By analyzing ~600 million microbial proteins from genomes and metagenomes, we mapped the full landscape of TIR-based immune signaling in bacteria and archaea. We identified >10,000 candidate Thoeris systems linked to proteins not previously recognized as Thoeris effectors.
Four Thoeris types were known, with three characterized, each relying on a different TIR-derived signal and effector protein to block phage infection.
TIR domains are ancient immune components found across the tree of life. In bacteria, they form the core of Thoeris, an antiviral system in which a TIR protein senses phage attack, produces an ADPR-derived immune signal, and activates effector proteins that block infection.
I’m happy to share our new preprint! We uncovered the full diversity of bacterial TIR-based antiviral immune signaling, massively expanded the known diversity of Thoeris systems, and revealed conservation of TIR-derived immune signals across the tree of life.
www.biorxiv.org/content/10.6...
Such a beautiful and well-rounded discovery, yet another exciting strategy in bacterial immunity. Congrats, Ilya!
Beautiful work Jeremy, It's exciting to see it out. Congrats!
📢 New preprint alert!
We designed synthetic proteins that can block bacterial immune systems, allowing phages + plasmids to overcome natural defenses.
This could transform phage therapy + genetic engineering.
Here’s what we found 🧵
Preprint🔗: www.biorxiv.org/content/10.1...
Preprint: De-novo design of proteins that inhibit bacterial defenses
Our approach allows silencing defense systems of choice. We show how this approach enables programming of “untransformable” bacteria, and how it can enhance phage therapy applications
Congrats Jeremy Garb!
tinyurl.com/Syttt
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