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

Abstract

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-1β 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-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. 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.

Innate Immune Evasion by Human Respiratory Syncytial Virus

“…However, the current knowledge regarding the NLRs, especially whether and how RSV blocks the NLRP3-mediated innate immune pathway, is still unknown. The present studies that characterize the role of NLRP3-mediated inflammasome are supposed to contribute mainly to RSV immunopathology and lung inflammation (Malinczak et al, 2021). NLRP3 inflammasome is suggested as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.…”

Bronchitis, COPD, and pneumonia after viral endemic of patients with leprosy on Sorok Island in South Korea

“…We correlated dapsone to compete with the NLRP3 inflammasome (Lee et al 2020a ). As NLRP3 plays a critical role in viral immunopathology (Malinczak et al 2021 ), we analyzed the relationship between bacterial respiratory diseases (RDs) and VRDs (Fig. S1 ).…”

Oxidative stress and ROS-mediated cellular events in RSV infection: potential protective roles of antioxidants

“…Many lines of evidence suggest that RSV can activate the NLRP3 inflammasome and induce inflammasome-related airway inflammation, even pyroptosis [ 70 , 76 , 77 ], similar to other RNA viruses [ 73 ]. As we mentioned before, RSV can induce excessive production of ROS [ 15 , 54 ], which contributes to the activation of the NLRP3 inflammasome in RSV infection (Fig.…”