Significance of RNA Sensors in Activating Immune System in Emerging Viral Diseases

Abstract

Viruses are known for their utilization of the host machinery to aid their replication within the infected cells. The viral nucleic acid, their intermittent forms contain pathogen-associated molecular patterns (PAMP) which enable the pattern recognition receptors (PRR) to distinguish them from self and mount a response against them. Highly robust targets for the PRRs are the cell entry points and phases of viral replication. RNA-sensing PRR can be classified as endosomal PRR and cytosolic PRR. Both enveloped and non-enveloped viruses utilize endosomal compartments to undergo proteolytic cleavage or pH-dependent conformational changes to ensure membrane fusion. Thus, monitoring the endosomal compartments in order to restrict the virus from penetrating into the cytoplasm is a key antiviral strategy. Endosomal compartments are guarded by Toll-like receptors (TLRs) which are the earliest discovered PRRs. TLR3, 7, and 8 specifically cater to viral RNA sensing. They can detect dsRNA and stable stem structures of ssRNA. Cytosolic PRRs include RIG-I like receptors (RLR) and nucleotide-binding oligomerization domain-containing (NOD)—like receptors (NLR). RLRs are cytosolic helicases which detect viral RNA, ds RNA, short 5′ppp RNA, and RNase L cleaved RNA. Retinoic acid-inducible gene I product (RIG-I), melanoma differentiation-associated antigen 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) are aspartate-glutamate-any amino acid-aspartate/histidine (DExD/H)-box helicases belonging to the SF2 superfamily. Other RNA helicases like SNRNP200 which belongs to the Ski-2 superfamily, or DDX60 belonging to the Ski-2-like helicase family are also involved in viral RNA sensing. NLRs like NLRP3 and NOD2 are cytosolic RNA-sensing PRRs. In addition to these, RNA-binding proteins like RNase L, protein kinase R (PKR), and interferon-inducible transmembrane protein (IFIT) are also present which play pertinent roles to enhance the antiviral immunity during a viral infection. Recognition of PAMPs or DAMPs by PRRs activate various signaling cascades which ultimately triggers the transcription of type I/III IFN, production of various pro-inflammatory cytokines, and various other genes that can ensure an intracellular antiviral state which will aid in containing the viral infection. Furthermore, these interferons can lead to the expression of multiple interferon-stimulated genes (ISGs) which induce antiviral activities controlling the life cycle of the virus, restricting its replication, and transmission to the surrounding cells. This chapter will elaborate on these RNA-sensing PRRs, their structures, agonists, mechanism of activation, and response mounted against viral infection.