For "U" the bell tolls: Pseudouridine evades TLR detection.

TLRs detect pathogen-derived uridine but not endogenous pseudouridine, which promotes host defense without autoimmunity. This principle is critical for the safe design of mRNA-based therapeutics, but the underlying mechanisms driving differential innate immune activation were unknown. In a recent issue of Cell, Bérouti et al.1 find that pseudouridine-containing RNA resists enzymatic degradation to evade TLR-mediated inflammation and type I interferon response.