The emerging role and significance of circular RNAs in viral infections and antiviral immune responses: possible implication as theranostic agents

Abstract

Circular RNAs (circRNAs) are ubiquitously expressed, covalently closed rings, produced by pre-mRNA splicing in a reversed order during post-transcriptional processing. Circularity endows 3′-5′-linked circRNAs with stability and resistance to exonucleolytic degradation which raises the question whether circRNAs may be relevant as potential therapeutic targets or agents. High stability in biological systems is the most remarkable property and a major criterion for why circRNAs could be exploited for a range of RNA-centred medical applications. Even though various biological roles and regulatory functions of circRNAs have been reported, their in-depth study is challenging because of their circular structure and sequence-overlap with linear mRNA counterparts. Moreover, little is known about their role in viral infections and in antiviral immune responses. We believe that an in-depth and detailed understanding of circRNA mediated viral protein regulations will increase our knowledge of the biology of these novel molecules. In this review, we aimed to provide a comprehensive basis and overview on the biogenesis, significance and regulatory roles of circRNAs in the context of antiviral immune responses and viral infections including hepatitis C virus infection, hepatitis B virus infection, hepatitis delta virus infection, influenza A virus infection, Epstein-Barr virus infection, kaposi's sarcoma herpesvirus infection, human cytomegalovirus infection, herpes simplex virus infection, human immunodeficiency virus infection, porcine epidemic diarrhoea virus infection, ORF virus infection, avian leukosis virus infection, simian vacuolating virus 40 infection, transmissible gastroenteritis coronavirus infection, and bovine viral diarrhoea virus infection. We have also discussed the critical regulatory role of circRNAs in provoking antiviral immunity, providing evidence for implications as therapeutic agents and as diagnostic markers.

Targeting circular RNAs as a therapeutic approach: current strategies and challenges

“…However, there are several limitations with RNAi molecules, including their rapid degradation by nucleases, low intracellular delivery efficiency, lack of cell-specificity, immunogenicity, and other off-target effects. 27 – 29 , 131 , 132 …”

A circular RNA derived from PLXNB2 as a valuable predictor of the prognosis of patients with acute myeloid leukaemia

“…Circular RNAs (circRNAs) are produced by back splicing and play a crucial role in both physiological and pathological processes [7][8][9], particularly cancer [10,11]. Based on accumulating evidence, circRNAs function through the following mechanisms: regulating gene expression in cis at the transcriptional level [12], acting as a microRNA "sponge" and inhibiting its function [13], interacting with RNA binding proteins that regulate transcription [14], encoding peptides [15], and other functions.…”

Circular RNA circDtx1 regulates IRF3-mediated antiviral immune responses through suppression of miR-15a-5p-dependent TRIF downregulation in teleost fish

“…Additionally, Cir-cRNA-5692 inhibits hepatocellular carcinoma by sponging miR-328-5p to enhance Disabled homolog 2-interacting protein expression [55]. Genes regulated by differentially expressed circular RNAs are involved in a variety of cellular processes, including apoptosis pathways, Janus-activated kinase signal transducers, and activators of transcription pathways, TLRs, and RLRs signaling pathways, and all of which are related to cellular immunity and viral pathogenesis [56]. Therefore, the regulatory mechanism of circRNAs in innate immune responses must be studied.…”