Discrimination of Self and Non-Self Ribonucleic Acids

Abstract

Most virus infections are controlled through the innate and adaptive immune system. A surprisingly limited number of so-called pattern recognition receptors (PRRs) have the ability to sense a large variety of virus infections. The reason for the broad activity of PRRs lies in the ability to recognize viral nucleic acids. These nucleic acids lack signatures that are present in cytoplasmic cellular nucleic acids and thereby marking them as pathogen-derived. Accumulating evidence suggests that these signatures, which are predominantly sensed by a class of PRRs called retinoic acid-inducible gene I (RIG-I)-like receptors and other proteins, are not unique to viruses but rather resemble immature forms of cellular ribonucleic acids generated by cellular polymerases. RIG-I-like receptors, and other cellular antiviral proteins, may therefore have mainly evolved to sense nonprocessed nucleic acids typically generated by primitive organisms and pathogens. This capability has not only implications on induction of antiviral immunity but also on the function of cellular proteins to handle selfderived RNA with stimulatory potential.

An inability to maintain the ribonucleoprotein genomic structure is responsible for host detection of negative-sense RNA viruses

“…The most prominent of these is the inherent immunogenicity of the viral uncapped RNA that is reliant on the interaction of RdRp or extensive secondary structure to protect its 5' end, together with the maintenance of high levels of NP to shield its genome (Gebhardt et al, 2017). As shown herein, small perturbations to the balance of NP availability showcases the fragility of this system and its general lack of robustness.…”

“…As a result of storing their genomic information in a manner that deviates from the central dogma, these viruses can be easily recognized by the host cell as 'non-self'. While the orientation of the RNA is not considered to be a pathogen-associated molecular pattern (PAMP), these genomic RNAs are generally unmodified on their 5' end and therefore begin with a 5' tri-phosphate motif that is a substrate for the pattern recognition receptor (PRR), RIG-I (Gebhardt et al, 2017). In addition to this PAMP, RNA viruses are generally also thought to generate a significant amount of double stranded RNA which can be recognized by the PRR, MDA5 (Schneider et al, 2014).…”

TheC. elegansRIG-I homologdrh-1mediates the Intracellular Pathogen Response upon viral infection

“…What happens downstream of DRH-1 activation to induce IPR gene expression? C. elegans does not have clear homologs of MAVS, IRF3, or NF-κB, which activate the transcriptional program downstream of RIG-I-like receptors in mammals (Gebhardt et al, 2017). Therefore, the signaling components that mediate this response in C. elegans are likely to be different.…”

“…After the helicase and CTD bind to viral RNAs, these receptors trigger a signaling cascade via interaction of the CARD domain with the mitochondrial activator of virus signaling (MAVS) protein, which ultimately results in the activation of the IRF3 and NF-B transcription factors (Wu and Hur, 2015). These transcription factors trigger downstream defense gene expression, including an IRF3-mediated antiviral type-I interferon response (Gebhardt et al, 2017). Given the importance of RLRs in antiviral defense and autoimmunity, further understanding their evolution and signaling mechanisms in different contexts could provide new avenues for treatment of viral infections and autoimmune diseases.…”

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

“…Cells detect infection by recognizing molecular patterns derived from pathogen's constituents (PAMPs) or cell damage (DAMPs). During viral infection, nucleic acid is a major signal that triggers the innate immune response, inducing a type one interferon (IFN-I)-mediated antiviral state (Gebhardt et al, 2017;Mansur et al, 2014). IFN-I binds to its cognate receptor and activates the JAK/STAT pathway, leading to expression of hundreds of interferon stimulated genes (ISGs) that make the intracellular environment hostile to viral replication in infected and proximal cells (Schoggins, 2019).…”