TIR-Domain Bacterial Antiphage Defense (Thoeris)

Discovery that bacteria use TIR (Toll/interleukin-1 receptor)-domain proteins as phage sensors within multi-gene defense systems -- the same domain family used by human Toll-like receptors (innate immunity signaling) and by SARM1 (the NAD+-depleting enzyme implicated in axonal degeneration), now understood to be evolutionarily related rather than superficially similar. Doron, Melamed, Ofir, Leavitt, Lopatina, Keren, Amitai & Sorek, "Systematic discovery of antiphage defense systems in the microbial pangenome" (Science 359, eaar4120, 2018-01-25, OpenAlex W2784532673, 1,402 citations) identified Thoeris (among nine other new defense systems) via large-scale comparative genomics of gene clusters flanking known defense genes. The specific NAD+-depletion biochemical mechanism (ThsB's TIR domain producing a signaling molecule that activates the ThsA effector) was elaborated in subsequent 2019-2022 work not independently re-verified for this node. Live drug-discovery programs already target SARM1 (neurodegeneration) and TLR agonism/antagonism (immuno-oncology, vaccine adjuvants) -- not yet its own industry, but a real, current "basic science not yet translated" case.