Central roles of NLRs and inflammasomes in viral infection

Abstract

The immune response to viral infections is determined by a complex interplay between the pathogen and the host. Innate immune cells express a set of cytosolic sensors to detect viral infection. Recognition by these sensors induces the production of type I interferons and the assembly of inflammasome complexes that activate caspase-1, leading to production of interleukin-1β (IL-1β) and IL-18. Here, I discuss recent progress in our understanding of the central roles of NOD-like receptors (NLRs) and inflammasomes in the immune response during viral infections. This information will improve our understanding of host defence mechanisms against viruses and provide new avenues for interfering in the pathogenesis of infectious diseases.

Figure 1. Intracellular sensors in innate immunity to viruses

Viral pathogen-associated molecular patterns (PAMPs) activate nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs) and inflammasomes to initiate signalling cascades that lead to the production of proinflammatory cytokines, thereby amplifying antiviral resistance. In the presence of viral PAMPS, NLRP3 and absent in melanoma 2 (AIM2) oligomerize and recruit ASC, the adapter protein engaged by inflammasomes through their pyrin (PYD) domains. The CARD domain within ASC binds the CARD domain of caspase-1, leading to caspase 1 activation and the production of interleukin-1β (IL-1β) and IL-18. Retinoic acid inducible gene-I (RIG-1) contains an RNA helicase domain and N-terminal CARD domains. The helicases senses the 5′ triphosphate moiety of RNA viruses and then signals via CARD–CARD interactions with the mitochondrial localized adapter molecule MAVS to the downstream IKK-related kinase, TBK1, which subsequently phosphorylates and activates IRF3 to turn on transcription of type I interferon (IFNα/β) genes. RIG-I also regulates IL-1β production transcriptionally and post-translationally following recognition of 5′-triphosphate dsRNA. Whereas RIG-I triggered transcription of pro-IL-1β is NF-κB-dependent and mediated by a MAVS, the caspase-1 inflammasome formation and IL-1β/IL-18 production by RIG-I involves ASC. The NLRs NOD2, NLRX1 and NLRC5 associate with MAVS. Whereas NOD2 mediates the induction of IFNα/β, NLRX1 and NLRC5 inhibit RIG-I–MAVS and thus negatively regulate type I IFN signalling. Both MAVS and caspase-1 signalling are blocked by influnenza NS1 protein.

Figure 2. Inflammasome pathways

The pattern recognition receptors (PRRs) nucleotide oligomerization and binding domain (NOD)-like receptor protein 3 (NLRP3), absent in melanoma 2 (AIM2) and retinoic acid inducible gene-I (RIG-I) assemble caspase-1-activating inflammasome complexes in response to microbial pathogen-associated molecular patterns (PAMPs). The NLRP3 inflammasome recognizes multiple PAMPs including viral RNA in combination with ATP, ion flux or reactive oxygen species. By contrast, AIM2 and RIG-I directly bind to dsDNA and ssRNA viral genomes, respectively. All three types of inflammasome induce caspase-1 activation and interleukin-1β (IL-1β) and IL-18 production. The adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) is essential in all inflammasome complexes to bridge the interaction between upstream PRRs and inflammatory caspases through its N-terminal pyrin domain (PYD) and C-terminal caspase-recruitment domain (CARD) motifs, respectively. To interfere with inflammasome signalling, the large genomes of poxviruses encode multiple inhibitors such as PYD and SPI-2 that inhibit ASC and caspase-1, respectively.