Abstract
Bacteria encode an arsenal of diverse systems that defend against phage infection. A common theme uniting many prevalent antiphage defense systems is the use of specialized nucleotide signals that function as second messengers to activate downstream effector proteins and inhibit viral propagation. In this article, we review the molecular mechanisms controlling nucleotide immune signaling in four major families of antiphage defense systems: CBASS, Pycsar, Thoeris, and type III CRISPR immunity. Analyses of the individual steps connecting phage detection, nucleotide signal synthesis, and downstream effector function reveal shared core principles of signaling and uncover system-specific strategies used to augment immune defense. We compare recently discovered mechanisms used by phages to evade nucleotide immune signaling and highlight convergent strategies that shape host-virus interactions. Finally, we explain how the evolutionary connection between bacterial antiphage defense and eukaryotic antiviral immunity defines fundamental rules that govern nucleotide-based immunity across all kingdoms of life.