Role of Toll-like receptor-induced short non-coding RNAs in innate immune response

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Project Summary and Abstract Infection of microbes causes a wide range of symptoms and diseases. Sustained efforts to understand the mechanism of cellular defense systems against microbe infections are essential to develop effective prevention methods and therapeutic applications. The innate immune system deploys various pattern-recognition receptors, including Toll-like receptors (TLRs), to recognize the invasion of microbes and initiate protective responses. TLRs are expressed at the cell surface or intracellular compartments (e.g., endosome and lysosome) in various cell types, such as macrophages, and recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) and peptidoglycan (PGN). The PAMP recognition initiates signal transduction pathways that culminate in the activation of transcription factors such as NF-κB, resulting in production of cytokines and chemokines to protect the host. Following transcriptional regulation, the downstream of TLR pathways involves regulation at multiple levels including post-transcription steps. In this context, short non- coding RNAs (ncRNAs) including those derived from transfer RNAs (tRNAs) have evolved as key post- transcriptional regulators. tRNA halves constitute a major subgroup of tRNA-derived ncRNAs and have been shown to be expressed as functional RNAs associated with various biological pathways and linked to human diseases such as neurodegenerative diseases and cancers. The goal of our proposed studies is to elucidate the expression profile and molecular function of tRNA half molecules whose accumulation is involved in the innate immune response. We recently found that the infection of Mycobacterium bovis BCG upregulates the expression of tRNA halves in human monocyte-derived macrophages (HMDMs). Furthermore, the expression of tRNA halves in HMDMs is upregulated by the activation of surface membrane TLRs, allowing us to define the tRNA halves as a novel class of TLR pathway-dependent tRNA halves. Importantly, tRNA halves are abundantly accumulated not only in TLR pathway-activated HMDMs but also in their extracellular vehicles (EVs) and have functional significance in activation of endosomal TLR pathway, suggesting that those tRNA halves are expressed as functional molecules promoting immune response. These results have led us to hypothesize that tRNA halves can be integral elements in the innate immune response. We propose to comprehensively identify the expression profiles of TLR pathway-induced tRNA halves in HMDMs and their EVs (Aim 1), to investigate the biogenesis mechanism how the production of tRNA haves are induced by TLR pathways (Aim 2), and to elucidate the molecular function of tRNA halves in endosomal TLR activation (Aim 3). Our study will reveal a novel tRNA-engaged ncRNA pathway in the innate immune response and may support the future exploration of biomarkers and efficacious therapeutic applications targeting tRNA half molecules upon microbe infection.