The phage-derived CBASS inhibitor can also bind the human cGAS immune enzyme and block its signaling activity, demonstrating once again that phage genomes are a rich reservoir of immune modulators capable of antagonizing bacterial, plant, and animal immunity 🦠🌿🧍‍♂️

Strikingly, one of the Thoeris inhibitors also binds and inhibits distantly related TIR domain proteins in humans and plants, suggesting that conservation between prokaryotic and eukaryotic immune proteins renders the eukaryotic homologs susceptible to phage-encoded inhibitors!

Acb3 neutralizes CD-NTase enzymes by wrapping around the immune protein, 'hugging' it tightly, and inserting a loop into its active site - blocking access to active sites that produce or recognize immune signals emerges as a common viral strategy for inhibiting signaling systems

The sixth family of anti-Thoeris proteins inserts decoy loops into the signal recognition site of the Thoeris effector and interacts with key residues that would otherwise bind the Thoeris immune signal

In the bacterial defense system Thoeris, infection stimulates TIR domains to produce an immune signaling molecule. We identified five families of anti-Thoeris proteins that bind Thoeris TIR proteins and insert flexible loops into their active sites to block signaling activity 🚫

We developed a computational and experimental pipeline that utilizes iterative structure predictions to analyze over 30M phage-encoded proteins for inhibitors that physically bind and antagonize host immune proteins ⚔️🛡️