An NLRP3 Variant Protects Against Severe COVID-19: An Unexpected Contribution of Inflammasome Genetics in SARS-CoV-2 Infection

Abstract

COVID-19, caused by the SARS-CoV-2 virus, manifests with varying degrees of severity, affecting individuals worldwide. The spectrum of symptoms ranges from mild to severe, with respiratory failure being a leading cause of death. Immunological factors, particularly excessive cytokine production such as IL-18 and IL-1β, significantly contribute to disease severity. In this context, the NLRP3 inflammasome, a key component of the innate immune system, has influenced COVID-19 outcomes. This study investigated the association between single-nucleotide variants (SNVs) in the NLRP3 inflammasome and COVID-19 severity. A case–control study was conducted involving 800 adult participants infected with SARS-CoV-2, stratified into mild/moderate and severe/critical cases. Genetic associations were assessed through qPCR-based genotyping. While no association was found between SNVs in IL1B and CASP1 with COVID-19 severity, the multivariate analysis revealed that the gain-of-function SNV in the NLRP3 gene (rs35829419) was associated with a protective effect against COVID-19–related mortality. These findings suggest that genetic variations in the NLRP3 inflammasome may modulate the host response to SARS-CoV-2, highlighting potential biomarkers for disease prognosis.