Role of rRNA-derived 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-B, 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) have evolved as key post-transcriptional regulators. Among various short ncRNA species, those from ribosomal RNAs (rRNAs), termed rRNA fragments (rRFs), are the most abundant class of short ncRNAs and have recently gained increasing attentions on their expression and functional significance. rRFs are constitutively expressed in multiple organisms including humans, and their expression is involved in regulation of cell cycle and proliferation, apoptosis, and lipid and glucose metabolism. In humans, their expression is modulated in a sex- and population-specific manner, and associated with type 2 diabetes and other diseases. We propose that rRFs play important roles in innate immune response. In preliminary studies, we found that the expression of rRFs is upregulated by the activation of surface TLR in human monocyte-derived macrophages (HMDMs). Importantly, short ncRNA sequencing data demonstrated the abundant accumulation of the rRFs not only in HMDMs but also in their secreted extracellular vehicles (EVs). Further experiments showed that a specific extracellular rRF activates endosomal TLR in the recipient HMDMs to induce cytokine secretion, suggesting that rRFs are not just accumulated as degradation by-products of rRNAs, but are accumulated as functional molecules promoting immune response. In the proposed studies, we will identify the expression profiles of TLR pathway-induced rRFs in HMDMs and their EVs (Aim 1). We will further elucidate the molecular function of extracellular rRFs in endosomal TLR activation (Aim 2). Finally, we will characterize the rRF expression in plasma samples from healthy subjects and patients infected with Mycobacterium tuberculosis (Aim 3). By defining a novel class of TLR pathway-induced rRFs and further establishing their roles, our study will reveal a novel rRNA-engaged ncRNA pathway in the innate immune response and may support the future exploration of biomarkers and efficacious therapeutic applications targeting ncRNAs upon microbe infection.