Interplay between innate immunity and negative-strand RNA viruses: towards a rational model

Abstract

The discovery of a new class of cytosolic receptors recognizing viral RNA, called the RIG-like receptors (RLRs), has revolutionized our understanding of the interplay between viruses and host cells. A tremendous amount of work has been accumulating to decipher the RNA moieties required for an RLR agonist, the signal transduction pathway leading to activation of the innate immunity orchestrated by type I interferon (IFN), the cellular and viral regulators of this pathway, and the viral inhibitors of the innate immune response. Previous reviews have focused on the RLR signaling pathway and on the negative regulation of the interferon response by viral proteins. The focus of this review is to put this knowledge in the context of the virus replication cycle within a cell. Likewise, there has been an expansion of knowledge about the role of innate immunity in the pathophysiology of viral infection. As a consequence, some discrepancies have arisen between the current models of cell-intrinsic innate immunity and current knowledge of virus biology. This holds particularly true for the nonsegmented negative-strand viruses (Mononegavirales), which paradoxically have been largely used to build presently available models. The aim of this review is to bridge the gap between the virology and innate immunity to favor the rational building of a relevant model(s) describing the interplay between Mononegavirales and the innate immune system.

Fig. 1.

Exclusion of self-RNA agonists of RLRs from the cytosol. The cytosol is kept free from any 5′ppp-ended RNA, with the exception of the 7SL RNA, the 5′ end of which is shielded by SRP components before exit from the nucleolus. All other nuclear transcripts either are capped with ribose 2′ O methylation and guanosine N-7 methylation or are cleaved shortly after the beginning of RNA synthesis. Mitochondrial transcripts do not exit from this organelle. The polymerase (RdRp) from cytosolic members of Mononegavirales produces capped mRNAs with ribose 2′ O methylation and guanosine N-7 methylation, as well as 5′ppp transcripts that are recognized by and activate RIG-I. These viruses also produce 5′ppp genomes and 5′ppp antigenomes. However, their 5′ppp termini are embedded in N protein subunits multimerized into the helicoidal nucleocapsid (not shown). (Adapted from reference with kind permission from Springer Science + Business Media.)

Fig. 2.

Model of RIG-I activation. (A) In its resting state, the RIG-I RD prevents CARD-mediated recruitment of downstream signaling factors. (B) Upon encountering a 5′ppp-dsRNA, the RIG-I helicase domain binds to the dsRNA and activates its ATP-dependent translocase activity. (C) This allows the RD to bind to the dsRNA blunt and 5′ppp ends. (D) 5′ppp recognition by the RD allows the CARDs to recruit downstream signaling factors.

Fig. 3.

Viral RNA species from measles virus as a prototype for Mononegavirales. (A) RNA products involved in virus replication. The viral polymerase enters at the 3′ end of the encapsidated genome to transcribe successively the 6 genes. In the case of the antigenome, only the trRNA is transcribed. All of the transcripts except the leRNA and trRNA are capped, ribose O methylated, and polyadenylated. The transcriptase pauses at every intergenic junction to polyadenylate and terminate the upstream transcript and then resumes transcription of the downstream transcript, except at the end of L gene, where transcription stops at the L polyadenylation site. Replication differs from transcription by continuous RNA synthesis (i.e., intergenic junctions are ignored), lack of capping and polyadenylation, and concomitant encapsidation of the newly synthesized RNA into a regular polymer of N protein. (B) Potential source of 5′ppp-dsRNA due to transcriptase and/or replicase errors. Note that any free 5′ppp-ssRNA can have secondary structures resulting in 5′ppp-dsRNA moieties.

Fig. 4.

Uniqueness of RNA synthesis by Mononegavirales. (A) Viral polymerase L and its cofactor P is unable to synthesize RNA on naked genomic RNA. (B) The genome (and antigenome) is entirely covered by a continuous noncovalent polymer of N protein subunits. P anchors L polymerase onto the nucleocapsid template and mediates its traveling along the nucleocapsid while transcribing (upper chart) or replicating (lower chart). See the legend to Fig. 3 for details of the RNAs that are produced.

Fig. 5.

Viral evasion strategies to escape detection. T-ended red lines indicate either blockade or competition for binding, with dashed lines for reported but not formally proved mechanism of action. Black dashed arrows indicate pathways and/or shuttling. P in red circles indicates phosphorylation. See the text for further details and references.

Fig. 6.

Viral evasion strategies to prevent activation of an antiviral state mediated by type I IFN binding to IFNAR. T-ended red arrows indicate either blockade or competition for binding. Black dashed arrows indicate pathways and/or shuttling. P in red circles indicates phosphorylation. Ub, ubiquitin. See the text for further details and references.

Fig. 7.

Primary role of the RLR/IPS-1 pathway in the control of lung infection by paramyxoviruses. (Top) Intranasal infection of normal mice with NDV results in IFN-α activation by the alveolar macrophages (AM) and conventional dendritic cells (cDC), leading to a limited virus burden locally with rapid virus clearance; consequently, local plasmacytoid DCs (pDC) are poorly activated to produce IFN-α. (Middle) In infected Myd88^−/− mice, the deficient TLR/Myd88 pathway prevents pDC from producing IFN-α. The virus burden, IFN-α production, and virus clearance are subnormal. (Bottom) In infected IPS-1^−/− mice, the deficient RLR/IPS-1 pathway prevents both AM and cDCs from producing IFN-α. The virus burden increases, and the IFN-α production and virus clearance are delayed. (Based in part on data from reference .)

Fig. 8.

Influence of route of inoculation on the ability of VSV to invade mouse brain. (A) Neuroinvasion from nasal infection with VSV; (B) mechanism preventing neuroinvasion after peripheral inoculation with VSV. See the text for details and references.