NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1 beta production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3-/-) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1 beta, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-beta. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

Automated summary

The activation of NLRP3 inflammasome plays a critical role in the pathogenesis of RSV infection, with inhibition leading to reduced lung immunopathology, mucus-associated gene expression, innate cytokine production, and inflammatory cell infiltration while increasing IFN-beta production. Inhibiting or deleting NLRP3 also diminishes viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation, demonstrating its potential as a therapeutic target for severe RSV disease and childhood asthma prevention.