Role of small RNAs in innate immunity and inflammation

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DESCRIPTION (provided by applicant): ROLE OF SMALL RNAS IN INNATE IMMUNITY AND INFLAMMATION Host responses against viruses involve activation of both innate and adaptive immune mechanisms. Viral persistence, caused by impaired host defense responses, is a common cause of inflammation. Several studies have indicated that presence of pathogens can stimulate inflammation-mediated tumor development. Thus, our long term goal is to understand the regulation of host signaling mechanisms that are involved in antiviral responses and how chronic inflammation arising from dysregulation of innate immune processes can promote tumorigenesis. Viruses are recognized in infected cells by the nucleic acid- recognizing Toll-like receptors (TLRs) or the cytosolic Rig-I-like receptors (RLRs). Early response to viruses includes production of type I interferon (IFN), which in turn induces the transcription of IFN-stimulated genes (ISGs) and activates enzymes that impede viral replication. Viral infections also upregulate other cytokines that can augment both innate and adaptive immune responses. During viral infections, double stranded RNAs (dsRNAs), representing viral genomes or produced as replicative intermediates, activate the IFN- inducible 2',5'- oligoadenylate synthetases (OAS), which convert cellular ATP to unique 2',5'- linked oligoadenylates, 2-5A. Trimeric and tetrameric oligomers of 2-5A activate a ubiquitous and latent endoribonuclease, RNase L, which cleaves viral and cellular single-stranded regions of RNA at the 3'end of UpAp and UpUp moieties, thereby releasing small RNAs with duplex structures. We recently reported that these small 'self'RNAs (cleavage products of cellular RNA generated by the action of RNase L) can amplify antiviral innate immunity by inducing IFN-¿ synthesis. Our preliminary data have led us to hypothesize that small RNAs generated by activation of RNase L also induces pro-inflammatory cytokines and pro-apoptotic pathways. This hypothesis is based on the observations that activation of RNase L 1) induces transcription of ISGs and antitumor genes, 2) induces chemokines and cytokines and 3) activates apoptotic signaling pathways. Identification of the relevant small RNAs involved with this process could provide a basis for development of novel antitumor and antiviral therapeutic strategies. The specific aims are: 1) Investigate the signaling pathway initiated by small RNA cleavage products of RNase L. 2) Clone and identify small cellular RNA generated by RNase L. 3) Develop small RNAs as immune stimulants. Understanding the role of small RNAs generated by RNase L in host response can provide new strategies to suppress viral infection and inflammation. PUBLIC HEALTH RELEVANCE: Excessive host response to virus may lead to uncontrolled inflammation leading to tissue damage and possible autoimmune responses, while an inadequate response allows viral spread and its associated cytopathicity. Our work focuses particularly on the role of the host protein RNase L in innate immune responses, and in this grant we hope to provide further understanding of the role of RNase L-generated small RNAs in inducing proinflammatory cytokines and anti-tumor or pro-apoptotic genes.