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

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.