Inflammasome Genetic Variants Are Associated with Protection to Clinical Severity of COVID-19 among Patients from Rio de Janeiro, Brazil

Abstract

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.

Innate Immune Gene Polymorphisms and COVID-19 Prognosis

“…Presence of the polymorphism results in a substitution of phenylalanine by isoleucine at position 102 in the classical transcript variant 1 of CARD8 gene (NM_001184900.3), although it could lead to a termination codon in other splicing variants of the gene (transcript variants 12, 14, and 17–19; , accessed on 12 July 2023). Similar to the study conducted by de Sá et al [ 41 ], in our cohort we observed a protective effect of CARD8 -rs2043211 polymorphism in COVID-19 severity ( Table 4 ); however, this finding was lost in multivariate analysis ( Table 5 ).…”

MicroRNA 205-5p and COVID-19 adverse outcomes: Potential molecular biomarker and regulator of the immune response

“…Other studies have shown that genetic variants of the NLPR3 inflammasome can influence the individual response to SARS-CoV-2 infection, which emphasizes that the activation of NLPR3 plays a key role during the inflammatory response. 29,30 Yet, this is the first time that the highly expressed circulating miRNA was proposed as a positive regulator of NLPR3 during COVID-19 due to the inhibition of the BCL6 repressor, and as a biomarker of COVID-19 severity.…”

“…In addition to the pro-inflammatory effect of miR-205-5p by increasing NLPR3 expression, this miR has been previously implicated in antiangiogenic effects in diabetes-induced limb ulcer. 30 High levels of circulating miR-205-5p have been found to decrease protein levels of vascular endothelial growth factor A (VEGFA) through direct binding on its 3′UTR mRNA in “in vitro” and “in vivo” models. 31 VEGFA is one of the most important members of the VEGF family, 32 and its angiogenic activity is strongly induced by hypoxia.…”

Inflammasome-Related Genetic Polymorphisms as Severity Biomarkers of COVID-19

“…Given the evident participation of the inflammasome in SARS-CoV-2 infection, it is plausible to think that inflammasome-related genes could provide new perspectives for illuminating the pathological processes potentially influencing the worsening and increased mortality of patients with this devastating disease. In fact, previous reports have suggested that the genetic variants related to the inflammasome are involved in the susceptibility or progression of COVID-19 disease [19][20][21][22][23][24][25]. However, our understanding of the complex interconnection between SARS-CoV-2 and inflammasome-related genes is still incomplete.…”