Innate Immunity Never “NODs” Off: NLRs Regulate the Host Anti-Viral Immune Response

A robust innate immune response is essential in combating viral pathogens. However, it is equally critical to quell overzealous immune signaling to limit collateral damage and enable inflammation resolution. Pattern recognition receptors are critical regulators of these processes. The cytosolic nucleotide-binding domain leucine-rich repeat (NLR; NOD-like receptor) family of pattern recognition receptors plays essential roles in the sensing of viral pathogen-associated molecular patterns and is best characterized for itsr pro-inflammatory biological functions. Specifically, these include the formation of multi-protein complexes, defined as inflammasomes or NODosomes that regulate the production of IL-1beta, IL-18, and pyroptosis, or the induction of NF-ΚB signaling. While these biological effects are inherently pro-inflammatory, it is also important to recognize that other NLR family members conversely function to negatively regulate inflammation through modulating signaling initiated by other families of pattern recognition receptors. Mechanistically, these unique NLRs also form multiprotein complexes that act to attenuate a variety of biological signaling pathways, such as the inhibition of NF-ΚB. This inhibition facilitates inflammation resolution and functions to restore cellular homeostasis. Despite extensive characterization of individual NLR family members, the mechanisms of immune system regulation are highly nuanced and remain enigmatic. This is especially true for non-inflammasome-forming, regulatory NLRs. Here, we discuss recent findings associated with NLR family members that play essential roles in the host immune response to viruses and mechanisms by which these pattern recognition receptors may function to regulate antiviral immunity.