Bacterial TIR-based immune systems sense phage capsids to initiate defense.

Thoeris systems use proteins with Toll/interleukin-1 receptor domains to protect prokaryotes from phage infection through the synthesis of a cyclic adenosine diphosphate ribose signalling molecule, which activates an effector that depletes the host of the essential metabolite NAD(+) to limit viral propagation. How infection is recognized during Thoeris immunity is not known. Here we investigate the staphylococcal Thoeris defense system, ThsA-B1-B2, and found that, upon infection, the major capsid proteins of Siphoviridae phages from serogroup B, but not A, form a complex with ThsB1 and ThsB2 to activate Thoeris defense. Thoeris cyclases from Streptococcus also recognize major capsid proteins. Our results suggest that the accumulation of capsid mutations that enable avoidance of Thoeris recognition may be an important evolutionary force behind the structural diversity of prokaryotic viruses. More broadly, given that some mammalian immune pathways contain Toll/interleukin-1 receptor domains that recognize viral structures, our findings highlight a conserved mechanism of innate antiviral immunity.