Interferon responses to norovirus infections: current and future perspectives

Figures

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  Fig. 1.. Mechanism of IFN induction in norovirus-infected cells. Pathogen-associated molecular patterns (PAMPs), generated from virus replication, are thought to be detected by MDA5 and NLRP6, leading to activation of MAVS at mitochondria and peroxisomes. Activated MAVS in turn activates downstream kinases, TBK1 and IKKε, which recruit and phosphorylate IRF3 and IRF7. This results in their dimerization and translocation into the nucleus, where they induce expression of type I and type III interferons. The interferons produced are then released to act on cells in an autocrine and paracrine manner. Although clear experimental evidence is lacking, it is likely that additional pattern recognition receptors, such as RIG-I, cGAS and/or others, contribute to the sensing of norovirus PAMPs. For example, RIG-I is able to detect transcripts generated by the norovirus polymerase when over-expressed in cells, and cGAS can sense leaked mitochondrial DNA that results from IL-1β signalling.

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  Fig. 2.. Possible PAMPs detected in norovirus-infected cells. Replication of noroviruses in the host cell likely generates PAMPs detected by intracellular PRRs. Although the identities of these PAMPs are yet to be determined, it is possible they include the double-stranded RNA intermediate composed of the VPg-linked positive-strand RNA and the de novo-synthesized negative-strand RNA, which may be detected by MDA5 (1). Single-stranded negative sense RNA intermediates that are likely not VPg-linked, produced during replication, could also be potential ligands for other host PRRs such as RIG-I (2). Additionally, MDA5, and perhaps RIG-I, may recognise RNA species transcribed by the viral polymerase from host RNA templates (3). And lastly, it is possible that MDA5 or RIG-I can detect RNA fragments produced by RNAse L digestion of host and viral RNA in norovirus-infected cells (4).

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  Fig. 3.. Evasion of IFN responses by noroviruses. Several strategies have been demonstrated or proposed through which noroviruses counteract the different stages of the host IFN response. (1) Avoidance of detection: certain strains of mouse and human noroviruses appear to induce very low levels of IFNs in infected cells, possibly by avoiding detection of viral ligands by host receptors, through yet unknown mechanisms. (2) Impairment of PRR functions: the NS3 protein may inhibit IFN induction by redistributing host GEF-H1, thus perhaps impeding the functions of host receptors of viral ligands. (3) Inhibition of the signalling cascade: the VF1 accessory protein inhibits IFN induction downstream of TBK1, through a yet unknown mechanism. (4) Obstruction of IFN release: the NS1/2 and NS4 proteins promote Golgi disassembly and disruption of ER-Golgi trafficking, thereby potentially impairing cellular secretory pathways utilized for release of IFNs. Other unknown factors in some strains of norovirus may also impair IFN release. (5) Disruption of IFN signalling and the antiviral state: the NS1 protein mediates persistence in type I IFN-resistant IECs and neutralises type III IFN signalling. The…