NLRP3 Inflammasome Activation in Viral Infections

The NLRP3 inflammasome is a multiprotein complex assembled around the NOD-like receptor NLRP3, the adaptor ASC and the cysteine protease caspase-1. It orchestrates the maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18 and induces pyroptotic cell death in response to viral invasion. Activation proceeds via a two-signal model. Signal 1 or priming arises from pathogen-associated molecular patterns (PAMPs) recognised by Toll-like receptors, RIG-I-like receptors or other sensors, culminating in NF-κB–driven upregulation of NLRP3 and pro-cytokines. Signal 2 involves a diverse array of triggers including danger-associated molecular patterns (DAMPs), ionic flux, reactive oxygen species, viral viroporins and host-derived molecules, which promote NLRP3 oligomerisation, ASC recruitment and caspase-1 activation. While NLRP3-driven responses are crucial for limiting viral replication, excessive or prolonged activation underlies immunopathology in conditions such as severe influenza A infection, hepatitis C and herpesvirus encephalitis. Many viruses have evolved strategies to evade or modulate the inflammasome, for instance by proteolytic cleavage or ubiquitination of NLRP3. Therapeutic modulation of this pathway using specific inhibitors or host-directed antiviral agents offers promise in mitigating cytokine storms and tissue damage. Ongoing research seeks to refine our understanding of inflammasome regulation to inform vaccine adjuvant development and targeted therapies against emerging viral threats.

Research from Nature Portfolio

Temporal inhibition of NLRP3 with a selective small-molecule antagonist during lethal influenza A virus challenge revealed a dual role for the inflammasome in disease. Early blockade exacerbates viral susceptibility, whereas delayed treatment at peak illness confers protection against severe lung inflammation and mortality. This work highlights the importance of treatment timing and suggests that controlled modulation of NLRP3 activation can reduce immunopathology without compromising antiviral defence.

NLRP3 Inflammasome Activation in Viral Infections publication trend

The graph below shows the total number of articles in nlrp3 inflammasome activation in viral infections across all publications each year (not limited to Nature Index journals).

Technical terms

NLRP3 inflammasome: Multiprotein innate-immune complex of NLRP3, ASC and caspase-1 that processes IL-1β and IL-18.

ASC: Adaptor apoptosis-associated speck-like protein that bridges NLRP3 and caspase-1 to enable inflammasome assembly.

Caspase-1: Cysteine protease activated within the inflammasome that cleaves pro-IL-1β and pro-IL-18 to their active forms.

PAMPs: Pathogen-associated molecular patterns such as viral RNA or proteins detected by pattern-recognition receptors to initiate immune priming.

DAMPs: Danger-associated molecular patterns including extracellular ATP, reactive oxygen species or ion flux released during cell stress or tissue damage.

Pyroptosis: Inflammatory form of programmed cell death executed by gasdermin-mediated pore formation downstream of inflammasome activation.

References

1. Gasdermin D promotes hyperinflammation and immunopathology during severe influenza A virus infection. Cell Death & Disease (2023).
2. Korean Chestnut Honey Suppresses HSV-1 Infection by Regulating the ROS–NLRP3 Inflammasome Pathway. Antioxidants (2023).
3. NLRP3 Inflammasome—A Key Player in Antiviral Responses. Frontiers in Immunology (2020).
4. Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition. Scientific Reports (2016).
5. IL-1β Production through the NLRP3 Inflammasome by Hepatic Macrophages Links Hepatitis C Virus Infection with Liver Inflammation and Disease. PLOS Pathogens (2013).