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Central roles of NLRs and inflammasomes in viral infection

Key Points

  • Inflammasomes and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) mediate the recognition of viruses by detecting evolutionarily conserved motifs in their genomic RNA or DNA. In addition to viral RNA, NLR family PYD-containing protein 3 (NLRP3) senses a large number of pathogen-associated molecular patterns (PAMPs) through incompletely characterized mechanisms, such as ion flux that is caused by viral ion channels or multiple coordinated signals.

  • Inflammasomes have a crucial role in the immune response to viral infections. NLR proteins were previously thought to be the only mediators of inflammasome activation. However, recent research has shown that members of additional cytoplasmic pattern-recognition receptor (PRR) families, such as retinoic acid inducible gene-I (RIG-I) and absent in melanoma 2 (AIM2), can activate the inflammasome in virus-infected cells.

  • NOD2, which was originally reported to activate mitogen-activated protein kinase and nuclear factor-κB signalling through receptor-interacting serine-threonine protein kinase 2 (RIPK2), in response to bacterial peptidoglycan, has been shown to also signal through mitochondrial antiviral signalling protein (MAVS) and to induce the production of type I interferons (IFNs) in response to viral single-stranded RNA.

  • NLR proteins also have regulatory functions during virus infection. NLRX1 negatively regulates type I IFN production that is mediated by the RIG-I–MAVS–IFN response factor 3 (IRF3) signalling cascade.

  • Crosstalk between innate immune signalling pathways has become increasingly evident. RIG-I was originally discovered as a mediator of type I IFN production but is now recognized as a potential inflammasome activator also.

  • Several viruses encode inhibitors of inflammasome and MAVS signalling pathways, thereby indicating an important role for these pathways in controlling virus replication and the requirement for viruses to interfere with their activation to successfully infect a host.

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.

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Figure 1: Intracellular sensors in innate immunity to viruses.
Figure 2: Inflammasome pathways.

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Acknowledgements

I acknowledge the large number of researchers who have contributed to this field and whose work was not cited or was cited through others' review articles because of space limitations. This work is supported by National Institute of Health grants AR056296 and AI088177, a NIAMS Centers of Excellence for Influenza Research and Surveillance (CEIRS) grant and the American Lebanese Syrian Associated Charities (ALSAC).

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Glossary

Pattern-recognition receptors

(PRRs). Receptors that bind molecular patterns that are found in pathogens, but not mammalian cells. Examples include the mannose receptor and Toll-like receptors.

Pathogen-associated molecular pattern

(PAMP). A molecular pattern that is found in pathogens, but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA, that bind Toll-like receptors.

Nucleotide-binding oligomerization domain (NOD)-like receptors

(NLRs). A large family of cytosolic pattern recognition receptors that resemble a subset of plant disease-resistance (R) genes, which are involved in the hypersensitive response against virulent plant pathogens. There are 22 NLR genes in the human genome and at least 34 NLR genes in the mouse genome. NLRs are involved in innate immune sensing and in the regulation of inflammatory and cell death responses.

NOD motif

Members of the nucleotide-binding oligomerization domain (NOD)-like receptor family and plant disease-resistance (R) gene products contain a central domain that is known as a NOD.

Hypersensitive response

A form of programmed cell death. The hypersensitive response is a marker of disease resistance in plants and is characterized by rapid, localized pathogen-induced cell death and restriction of further pathogen growth.

Caspases

Caspases are evolutionarily conserved cysteine proteases that are synthesized as inactive zymogens. After proteolytic activation, they initiate or execute cellular programmes leading to inflammation or cell death. Caspases are categorized as either pro-inflammatory or pro-apoptotic, depending on their participation in these cellular programmes. The inflammatory caspases are caspase-1, caspase-11 and caspase-12 in mice and caspase-1, caspase-4, and caspase-5 in humans.

Danger-associated molecular pattern

(DAMP). A conserved mammalian motif, recognized by pattern recognition receptors, that is broadly upregulated in response to cellular stress and that triggers an innate immune response. Examples include heat shock proteins, high motility group box 1 protein (HMGB1), DNA-binding proteins and uric acid.

Autophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation through fusion to secondary lysosomes.

Inflammasome

A large multiprotein complex containing certain nucleotide-binding oligomerization domain (NOD)-like receptor (NLR), retinoic acid inducible gene-I (RIG-I)-like receptor (RLR) and IFI200 proteins, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1. Assembly of the inflammasome leads to the activation of caspase-1, which cleaves pro-interleukin-Iβ (pro-IL-1β) and pro-IL-18 to generate the active pro-inflammatory cytokines.

Small interfering RNA

(siRNA). Synthetic double-stranded RNA molecules of 19–23 nucleotides, which are used to 'knockdown' (silence the expression of) a specific gene. This is known as RNA interference and is mediated by the sequence-specific degradation of mRNA.

Pyroptosis

A form of cell death that is associated with antimicrobial responses during inflammation and is dependent on the activation of an inflammasome and inflammatory caspases such as caspase-1.

K63-linked polyubiquitylation

Ubiquitin is a highly conserved 76 kDa protein that is ligated to many proteins in both monomeric and polymeric forms. The two most common ubiquitin polymer chains are linked through an isopeptide bond between glycine-76 and either lysine-48 (K48) or lysine-63 (K63). K63-linked polyubiquitylation results in signals that are related to intracellular trafficking, cell signalling, ribosomal biogenesis and DNA damage repair. There are also reports that K63-linked polyubiquitin chains are involved in proteasome-independent proteolysis through autophagy.

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Kanneganti, TD. Central roles of NLRs and inflammasomes in viral infection. Nat Rev Immunol 10, 688–698 (2010). https://doi.org/10.1038/nri2851

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