Systematic phylogenetic analysis reveals that at least 90 structurally distinct prokaryotic STAND NTPase families provide antiviral defense by recognizing most core structural and replicative proteins of tailed phages through shape-complementary pattern recognition, with multiple families independently evolving to sense the same essential phage components such as the major capsid protein, and some systems repurposing abundant host factors like elongation factor Tu to enhance immune complex assembly and nuclease activity.

Recognition of foreign molecules inside cells is critical for immunity across all domains of life. Proteins of the STAND NTPase superfamily, including eukaryotic NOD-like receptors (NLRs), play a central role in this process. In bacteria and archaea, although several STAND families sense phage proteins, their functional diversity remains largely unexplored. We conducted a systematic phylogenetic analysis of prokaryotic STAND NTPases and identified at least 90 structurally distinct families associated with antiviral defense. We first show that the uncharacterized Avs7 family recognizes the major capsid protein (MCP) of tailed phages. Three cryo-EM structures of Salmonella enterica Avs7 reveal an asymmetric, butterfly-shaped tetramer that assembles stepwise via large, MCP-induced conformational changes, incorporating bacterial elongation factor Tu (EF-Tu) as a structural component that enhances defense. Using genetic screens with a library of 687 phage genes, we further show that 13 additional STAND families sense 13 conserved phage proteins, encompassing most of the core structural and replicative components of tailed phages. These include two distinct MCP-sensing families—Avs8 (PD-λ-4) and Avs10 (Erebus/Hypnos/bNACHT64)—and 11 others (Avs11–21) recognizing the portal, portal adaptor, tail nozzle, head–tail connector, tail terminator, tail tube protein, tail assembly chaperone, tape measure protein, DNA polymerase, helicase/RecA-type ATPase, and single-stranded DNA annealing protein, respectively. Together, our findings highlight structurebased pattern recognition and host factor repurposing as fundamental strategies of bacterial immunity.