Bacteriophages inhibit and evade cGAS-like immune function in bacteria

A fundamental strategy of eukaryotic antiviral immunity involves the cGAS enzyme, which synthesizes 2',3'-cGAMP and activates the effector STING. Diverse bacteria contain cGAS-like enzymes that produce cy-clic oligonucleotides and induce anti-phage activity, known as CBASS. However, this activity has only been demonstrated through heterologous expression. Whether bacteria harboring CBASS antagonize and co -evolve with phages is unknown. Here, we identified an endogenous cGAS-like enzyme in Pseudomonas aer-uginosa that generates 3 ',3 '-cGAMP during phage infection, signals to a phospholipase effector, and limits phage replication. In response, phages express an anti-CBASS protein (Acb2) that forms a hexamer with three 3',3'-cGAMP molecules and reduces phospholipase activity. Acb2 also binds to molecules pro-duced by other bacterial cGAS-like enzymes (3 ',3 '-cUU/UA/UG/AA) and mammalian cGAS (2',3'-cGAMP), suggesting broad inhibition of cGAS-based immunity. Upon Acb2 deletion, CBASS blocks lytic phage repli-cation and lysogenic induction, but rare phages evade CBASS through major capsid gene mutations. Alto-gether, we demonstrate endogenous CBASS anti-phage function and strategies of CBASS inhibition and evasion.

Automated summary

This article discusses bacterial resistance to phages through the production of cGAS-like enzymes and the discovery of phages evading bacterial resistance through the expression of anti-CBASS proteins. Through deletion experiments of Acb2 protein, it was found that CBASS can block phage replication and lytic induction, but some phages escape CBASS through major capsid gene mutations.