Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure

A complex interaction exists between elements of the host innate immune system and viral pathogens. It is essential that the host mount a robust immune response during viral infection and effectively resolve inflammation once the pathogen has been eliminated. Members of the nucleotide-binding domain leucine-rich repeat [NBD-LRR; known as NOD-like receptor (NLR)] family of cytosolic pattern-recognition receptors are essential components of these immunological processes and have diverse functions in the host antiviral immune response. NLRs can be subgrouped based on their general function. The inflammasome-forming subgroup of NLRs are the best-characterized family members, and several have been found to modulate the maturation of IL-1β and IL-18 following virus exposure. However, the members of the regulatory NLR subgroups are significantly less characterized. These NLRs uniquely function to modulate signalling pathways initiated by other families of pattern-recognition receptors, such as Toll-like receptors and/or Rig-I-like helicase receptors. Regulatory NLRs that augment pro-inflammatory pathways include nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD2, which have been shown to form a multiprotein complex termed the NODosome that significantly modulates IFN and NF-κB signalling following viral infection. Conversely, a second subgroup of regulatory NLRs functions to negatively regulate inflammation. These inhibitory NLRs include NLRX1, NLRP12 and NLRC3, which have been shown to interact with TRAF molecules and various kinases to modulate diverse cellular processes. Targeting NLR signalling following infection with a virus represents a novel and promising therapeutic strategy. However, significant effort is still required to translate the current understanding of NLR biology into effective therapies.