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

Abstract

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 virus infection and effectively resolve inflammation once the pathogen has been eliminated. Members of the NBD-LRR (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. The NLRs can be sub-grouped based on their general function. The inflammasome forming sub-group 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 sub-groups are significantly less characterized. These NLRs uniquely function to modulate signaling pathways initiated by other families of pattern recognition receptors, such as Toll-like Receptors (TLRs) and/or Rig-I-like Helicase Receptors (RLRs). Regulatory NLRs that augment pro-inflammatory pathways include NOD1 and NOD2, which have been shown to form a multi-protein complex termed the NODosome that significantly modulates interferon and NF-κB signaling following viral infection. Conversely, a second sub-group 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 signaling following infection with 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.