Tricks and threats of RNA viruses - towards understanding the fate of viral RNA

Abstract

Human innate cellular defence pathways have evolved to sense and eliminate pathogens, of which, viruses are considered one of the most dangerous. Their relatively simple structure makes the identification of viral invasion a difficult task for cells. In the course of evolution, viral nucleic acids have become one of the strongest and most reliable early identifiers of infection. When considering RNA virus recognition, RNA sensing is the central mechanism in human innate immunity, and effectiveness of this sensing is crucial for triggering an appropriate antiviral response. Although human cells are armed with a variety of highly specialized receptors designed to respond only to pathogenic viral RNA, RNA viruses have developed an array of mechanisms to avoid being recognized by human interferon-mediated cellular defence systems. The repertoire of viral evasion strategies is extremely wide, ranging from masking pathogenic RNA through end modification, to utilizing sophisticated techniques to deceive host cellular RNA degrading enzymes, and hijacking the most basic metabolic pathways in host cells. In this review, we aim to dissect human RNA sensing mechanisms crucial for antiviral immune defences, as well as the strategies adopted by RNA viruses to avoid detection and degradation by host cells. We believe that understanding the fate of viral RNA upon infection, and detailing the molecular mechanisms behind virus-host interactions, may be helpful for developing more effective antiviral strategies; which are urgently needed to prevent the far-reaching consequences of widespread, highly pathogenic viral infections.

Keywords: RNA viruses; viral RNA degradation; viral RNA sensing; viral evasion.

Figure 1.

Cell signalling pathways that respond to viral RNA. During viral infection vRNA, single- or double-stranded, is introduced into the cell. This RNA is recognized by cellular sensors, RIG-I, MDA5, LGP2, PKR, OAS, TLR3/7/8, NLRP1, NOD2, and IFITs. Upon vRNA sensing, type I interferon response, as well as the production of antiviral IFN-stimulated genes (ISGs), is activated. Moreover, some vRNA sensors exert their function directly on viral RNA either by sequestrating viral transcripts from the pool of translationally active mRNAs (IFIT proteins) or by stimulating RNase L to degrade RNAs (OAS). Activation of PKR leads to phosphorylation of eukaryotic initiation factor eIF2α what subsequently results in global translation shutdown

Figure 2.

Structures of 7-methylguanosine RNA caps

Figure 3.

RNA viruses strategies either to avoid recognition by host cell immune system or to modulate cellular translation. Viruses use several methods to hide their genetic material from cellular RNA sensors. In order to do that viral RNA can undergo post-transcriptional modifications such as N6-methylation of adenosine (m⁶A), internal 2′-O-methylation (N_m), and cytosine-5-methylation (5mC). Moreover, to evade recognition by anti-viral immune system, on 5′ end of viral mRNA cap structure can be installed either by viral capping enzyme or through the ‘cap snatching’. RNA intermediates of viral replication can be hidden from host RNA sensors in specialized bodies called replication organelles (ROs). RNA viruses also learned how to lower the translation rate of cellular transcripts either by directly interfere with the biosynthesis of host proteins or by modulating RNA metabolism what in consequence leads to degradation of cellular transcripts