Bacteriophages antagonize cGAS-like immunity in bacteria

Summary The recently discovered c yclic-oligonucleotide- b ased a nti-phage s ignaling s ystem (CBASS) is related to eukaryotic cGAS-STING anti-viral immunity and is present in diverse prokaryotes. However, our understanding of how CBASS detects, inhibits, and co-evolves with phages is limited because CBASS function has only been studied in reconstituted heterologous systems. Here, we identify a phage-encoded CBASS antagonist ( acbIIA1, a nti- cb ass type II-A gene 1 ) necessary for phage replication in the presence of endogenous CBASS immunity in Pseudomonas aeruginosa . acbIIA1 homologs are encoded by numerous lytic and temperate phages infecting Gram-negative bacteria. Deletion of acbIIA1 renders multiple phages susceptible to CBASS, but phages can then escape immune function via mutations in the major capsid gene. These mutants suggest that CBASS is activated by, or targets, the late-expressed phage capsid. Together, we establish a native model system to study CBASS and identify a common phage-encoded CBASS antagonist, demonstrating that CBASS is a bona fide anti-phage immune system in nature. Graphical Abstract