To sense or not to sense viral RNA--essentials of coronavirus innate immune evasion

Abstract

An essential function of innate immunity is to distinguish self from non-self and receptors have evolved to specifically recognize viral components and initiate the expression of antiviral proteins to restrict viral replication. Coronaviruses are RNA viruses that replicate in the host cytoplasm and evade innate immune sensing in most cell types, either passively by hiding their viral signatures and limiting exposure to sensors or actively, by encoding viral antagonists to counteract the effects of interferons. Since many cytoplasmic viruses exploit similar mechanisms of innate immune evasion, mechanistic insight into the direct interplay between viral RNA, viral RNA-processing enzymes, cellular sensors and antiviral proteins will be highly relevant to develop novel antiviral targets and to restrict important animal and human infections.

Figure 1

Coronavirus genome organization. Schematic representation of the MHV genome and ORFs encoding for replicase (red boxes), structural (dark blue boxes) and accessory proteins (cyan boxes). Specific replicase domains and functions, including ExoN, N7-MTase, EndoU, and 2′O-MTase are depicted. Arrows represent polyprotein cleavage sites of papain-like proteinases (PL1 and PL2 proteinase; green) and chymotrypsin-like proteinase (3C-L proteinase; red).

Figure 2

Host innate immune responses to coronaviral methyltransferase-deficient mutants. Sensing of non-self RNA: CoVs lacking 2′O-MTase-activity induce a MDA5-dependent expression of type-I IFN in macrophages, indicating the 2′O-methylation on viral RNAs provides a signature that classifies these RNAs as ‘self’ RNAs. Since direct binding of MDA5 to capped RNA lacking 2′O-methylation (i.e. cap0) could not yet been demonstrated, it remains possible that additional factor(s) (depicted as X) may facilitate MDA5 activation. Non-self RNAs are proposed as RNAs lacking 2′O-methylation (sensing by MDA5), N7-methylation and 2′O-methylation (sensing is currently not known) and RNA comprising 5′-ends with triphosphates (sensing by RIG-I). Restriction of viral protein translation: 2′O-MTase-deficient viruses are sensitive to the antiviral actions of IFN and the IFN-induced protein IFIT1 was shown to bind RNA lacking 2′O-methylation and causing a translation arrest. It is currently unknown how CoVs lacking the N7-MTase activity will affect viral replication and if a similar translational arrest may occur. IFIT1 was shown to efficiently bind non-methylated RNA (i.e. lacking N7-methylation and 2′O-methylation). It remains to be clarified if other IFIT proteins or ISG are required for translational arrest.