The multifaceted roles of NAD⁺ in bacterial immunity

Bacteriophages impose significant evolutionary pressure on bacteria, driving the emergence of a diverse array of antiphage defense systems. A central player in many identified antiphage systems is nicotinamide adenine dinucleotide (NAD⁺). This review explores the multifaceted roles of NAD⁺ in bacterial immunity, from its function as an essential metabolite and substrate for enzymatic defense to its involvement in signal transduction pathways. We examine how antiphage systems manipulate NAD⁺ to block phage infection and, conversely, how phages employ counterdefense strategies targeting immune pathways that rely on NAD,⁺ or use NAD⁺ themselves to evade host immunity. Finally, we discuss the remarkable evolutionary conservation of these NAD⁺-centric immune actors and strategies in eukaryotic innate immunity. This highlights NAD⁺'s pivotal role in innate immunity across domains of life.