NLRP3 Inflammasome-A Key Player in Antiviral Responses

Abstract

The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and caspase-1. This complex is crucial to the host's defense against microbes as it promotes IL-1β and IL-18 secretion and induces pyroptosis. NLRP3 recognizes variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) generated during viral replication that triggers the NLRP3 inflammasome-dependent antiviral immune responses and facilitates viral eradication. Meanwhile, several viruses have evolved elaborate strategies to evade the immune system by targeting the NLRP3 inflammasome. In this review, we will focus on the crosstalk between the NLRP3 inflammasome and viruses, provide an overview of viral infection-induced NLRP3 inflammasome activation, and the immune escape strategies of viruses through their modulation of the NLRP3 inflammasome activity.

Keywords: NLRP3; antiviral immunity; inflammasome; viral evasion; viral infection.

Figure 1

NLRP3 inflammasome activation during viral infections. Activation of the NLRP3 inflammasome requires two signals. Signal 1 (priming signal): the activation of PRRs, TNFR, or IFNR induces NF-κB activation, triggers the transcription of NLRP3, pro-caspase-1, pro-IL-1β, and pro-IL-18. Signal 2 (activation signal): multiple DAMPs and PAMPs induce NLRP3 inflammasome assembly and activation. DAMPs include (a) lysosomal or endosomal injury, (b) aberrant ionic fluxes, (c) mitochondrial injury, and (d) protein aggregates. (e) With the help of DAI/ZBP1, DHX33, OAS, or DDX19A, NLRP3 is activated by sensing viral proteins and RNA. NLRP3 inflammasome activation leads to the auto-cleavage of pro-caspase-1. Caspase-1 then mediates the proteolytic process of pro-IL-1β, pro-IL-18, and gasdermin D (GSDMD).

Figure 2

Viral immune evasion strategies by targeting the NLRP3 inflammasome. (a) Influenza virus NS1 protein, measles virus, SeV, and Nipah virus V proteins prevent NRLP3 inflammasome assembly. PB1-F2 of IAV and miR-BART15 of EBV inhibit NLRP3 inflammasome activation. (b) EV71 proteases 2A and 3C and HPIV C protein induce NLRP3 protein degradation. (c) EV71 protease 3C and ZIKV NS1 protein modulate the effector function of the NLRP3 inflammasome by targeting GSDMD and caspase-1, respectively.