Bacterial transfer-messenger RNA activates antiviral RNA sensing to induce inflammatory innate immune responses

Abstract Pathogen-derived RNAs function as pathogen-associated molecular patterns (PAMPs) that activate innate immune responses through pattern recognition receptors (PRRs). While viral RNA is well established as a trigger of antiviral immunity, the identity of bacterial RNA species that function as immunostimulatory ligands and the host PRRs that recognize them remain poorly defined. Here, we identify bacterial-specific transfer-messenger RNA (tmRNA), a conserved RNA involved in ribosome rescue during bacterial trans-translation, as a previously unrecognized RNA PAMP. tmRNA robustly induced the production of IL-6, TNF-α, and IFN-α in murine Flt3 ligand-derived dendritic cells. Genetic analyses revealed that this response was dependent on the TLR7–MyD88 signaling pathway. Systemic administration of tmRNA in mice induced transient cytokinemia and inflammatory changes in the liver and lung, both of which were abolished in TLR7-deficient mice, demonstrating a critical role for TLR7 signaling in tmRNA-induced inflammation in vivo. In contrast, tmRNA failed to induce cytokine production in the human plasmacytoid dendritic cell line CAL-1 despite preserved responsiveness to the TLR7/8 agonist R848, suggesting that bacterial RNA sensing mechanisms may differ between murine and human immune cells. Together, these findings identify tmRNA as a bacterial RNA ligand capable of activating antiviral RNA-sensing pathways in murine immune cells; however, the relevance of these findings to human immune cells remains a limitation of the present study.