Bacteria sense virus-induced genome degradation via methylated mononucleotides

Phages often degrade the genome of their bacterial host to individual nucleotides and use these nucleotides to build their own genome. In this study, we describe a bacterial defense system that directly senses phage-mediated host genome degradation. This system, called Metis, aborts phage infection once it detects the accumulation of the modified mono-nucleotide N⁶-methyl-deoxyadenosine monophosphate (m⁶dAMP). As methylation of deoxy adenosines occurs only in the context of the DNA polymer, intracellular accumulation of m⁶dAMP serves as a definitive signal that the host genome has been degraded to its individual constituents. In type I Metis, sensing of m⁶dAMP activates an NAD⁺ diphosphatase, leading to rapid NAD⁺ depletion and cessation of the infection process; while the effector in type II Metis is a transmembrane-spanning protein whose toxicity is triggered in response to the modified mono-nucleotide. We further show that Metis defense depends on endogenous DNA methylases, and that phages can escape Metis via mutations that inactivate phage-mediated host genome degradation. Our results demonstrate how molecular byproducts released during virus-induced cell exploitation can be used as specific danger signals that trigger host immunity.