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COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic or mild/moderate symptoms to severe symptoms and death. The mechanisms underlying its clinical evolution are still unclear. Upon SARS-CoV-2 infection, host factors, such as the inflammasome system, are activated by the presence of the virus inside host cells. The search for COVID-19 risk factors is of relevance for clinical management. In this study, we investigated the impact of inflammasome single-nucleotide polymorphisms (SNPs) in SARS-CoV-2-infected individuals with distinct severity profiles at clinical presentation. Patients were divided into two groups according to disease severity at clinical presentation based on the WHO Clinical Progression Scale. Group 1 included patients with mild/moderate disease ( WHO < 6 ; n = 76 ), and group 2 included patients with severe/critical COVID-19 ( WHO ≥ 6 ; n = 357 ). Inpatients with moderate to severe/critical profiles were recruited and followed-up at Hospital Center for COVID-19 Pandemic – National Institute of Infectology (INI)/FIOCRUZ, RJ, Brazil, from June 2020 to March 2021. Patients with mild disease were recruited at Oswaldo Cruz Institute (IOC)/FIOCRUZ, RJ, Brazil, in August 2020. Genotyping of 11 inflammasome SNPs was determined by real-time PCR. Protection and risk estimation were performed using unconditional logistic regression models. Significant differences in NLRP3 rs1539019 and CARD8 rs2043211 were observed between the two groups. Protection against disease severity was associated with the A/A genotype ( OR adj = 0.36 ; P = 0.032 ), allele A ( OR adj = 0.93 ; P = 0.010 ), or carrier-A ( OR adj = 0.45 ; P = 0.027 ) in the NLRP3 rs1539019 polymorphism; A/T genotype ( OR adj = 0.5 ; P = 0.045 ), allele T ( OR adj = 0.93 ; P = 0.018 ), or carrier-T ( OR adj = 0.48 ; P = 0.029 ) in the CARD8 rs2043211 polymorphism; and the A-C-G-C-C ( OR adj = 0.11 ; P = 0.018 ), A-C-G-C-G ( OR adj = 0.23 ; P = 0.003 ), C-C-G-C-C ( OR adj = 0.37 ; P = 0.021 ), and C-T-G-A-C ( OR adj = 0.04 ; P = 0.0473 ) in NLRP3 genetic haplotype variants. No significant associations were observed for the other polymorphisms. To the best of our knowledge, this is the first study demonstrating an association between CARD8 and NLRP3 inflammasome genetic variants and protection against COVID-19 severity, contributing to the discussion of the impact of inflammasomes on COVID-19 outcomes.

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