Single-Nucleotide Variants in the AIM2 – Absent in Melanoma 2 Gene (rs1103577) Associated With Protection for Tuberculosis

Figueira, Mariana Brasil de Andrade; Lima, Dhêmerson Souza de; Boechat, Antônio Luiz; Filho, Milton Gomes do Nascimento; Antunes, Irineide Assumpção; Matsuda, Joycenea da Silva; Ribeiro, Thaís Rodrigues de Albuquerque; Felix, Luana Sousa; Gonçalves, Ariane Senna Fonseca; Costa, Allyson Guimarães; Ramasawmy, Rajendranath; Pontillo, Alessandra; Ogusku, Maurício Morishi; Sadahiro, Aya

doi:10.3389/fimmu.2021.604975

“…On the other hand, several studies of the genes involved in assembling inflammasome complexes have attempted to explain their role in the heterogeneity of disease. For the same infection, some individuals are more susceptible to developing the disease, while others remain asymptomatic [ 25 ]. The present study demonstrated that genetically specific profiles (alleles, genotypes, and haplotypes) of NLRP3 rs1539019 and CARD8 rs2043211 polymorphisms were associated with protection against disease severity in SARS-CoV-2-infected individuals.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammasome activation is strictly regulated by endogenous host proteins (e.g., CARD8 and HSP90) and by a variety of transcriptional and posttranscriptional mechanisms [ 24 ]. NLR inflammasomes comprise at least three components: a protein sensor (e.g., NLRP1 and NLRP3), an inflammatory caspase (e.g., caspase-1 and caspase-11), and an adapter molecule containing a CARD domain (e.g., ASC) [ 25 ]. In addition, twenty-two members of the NLR family have been described in humans and can be divided into four categories based on their functions: inflammasome formation, signal transduction, transcription activation, and autophagy [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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

Sá

¹

,

Neira-Goulart

²

,

Ribeiro-Alves

³

et al. 2022

BioMed Research International

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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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“…Several studies of genes involved in assembling the complex of in ammasomes have attempted to explain their role in the heterogeneity of diseases. For the same infection, some individuals are more susceptible to developing the disease while others remain asymptomatic (23). We showed here The NLRP3 in ammasome -also known as NALP3 and cryopyrin -is currently the most studied in ammasomes component, being considered the main study model of these cytoplasmic complexes.…”

Section: Discussionmentioning

confidence: 75%

“…In ammasome activation is strictly regulated by endogenous host proteins (e.g., CARD8 and HSP90) and by a variety of transcriptional and post-transcriptional mechanisms (22). In ammasomes belonging to the NLR are composed of at least three components: a protein sensor (e.g., NLRP1 and NLRP3), an in ammatory caspase (e.g., caspase-1 and caspase-11), and, nally, an adapter molecule containing a CARD domain (e.g., ASC) (23). It has been shown that proteins E, ORF3a e ORF8b from SARS-CoV activate NLRP3 in ammasome (15).…”

Section: Introductionmentioning

confidence: 99%

Nlrp3 Inflammasome Genetic Variants Are Associated With Risk And/Or Protection To Hospitalization Among Covid-19 Patients From Rio De Janeiro, Brazil

Sá

¹

,

Neira-Goulart

²

,

Ribeiro-Alves

³

et al. 2021

Preprint

0

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Background COVID-19 has a broad spectrum of clinical manifestations, from asymptomatic to mild or moderate symptoms, reaching the most severe forms and death. The mechanisms underlying the SARS-CoV-2 infection and its clinical evolution are still unclear. Once SARS-CoV-2 infects individuals, host factors are activated by the presence of the virus inside the cells, such as the inflammasome system. The search of risk factors for COVID-19 is of relevance for clinical management. In this study, we investigated the impact of 11 single-base polymorphisms (SNPs) in the NLRP3, CARD8, AIM2, CASP-1, IFI16, and IL-1β inflammasome genes in SARS-CoV-2 infected individuals with distinct disease outcomes. Methods Patients were divided into two groups: (1) inpatients, with severe/critical disease (Hospitalized group, n=451), and (2) convalescent volunteers with prior SARS-CoV-2 infection and a history of asymptomatic to mild symptoms (Mild group, n=43). Patients hospitalized were followed up at a Hospital Center for COVID-19 Pandemic – National Institute of Infectology (INI)/FIOCRUZ, Rio de Janeiro, Brazil, from June 2020 to March 2021. The Mild group was recruited at Oswaldo Cruz Institute (IOC)/FIOCRUZ, Rio de Janeiro, Brazil, in 2020. Genotyping of the SNPs was determined by Real-Time PCR. Protection and risk estimations were performed by unconditional logistic regression models. Results Among the genotyped SNPs, significant differences in the NLRP3 rs1539019 and rs10754558 frequencies were observed between the groups. The C/C genotype (ORadj=6.31; Padj=0.026) or allele C (ORadj=1.05; Padj=0.002) in rs1539019 polymorphism were associated with the risk for hospitalization, while the C/G genotype (ORadj=0.16; Padj=0.016) or carrier-G (ORadj=0.2; Padj=0.028) in rs10754558 polymorphism were associated with protection for hospitalization. Regarding the NLRP3 genetic variants, the A-C-G-C-G haplotype (ORadj=0.14; Padj= 0.030) was associated with protection for hospitalization. No significant association was observed for the other polymorphisms. Conclusions As of our knowledge, this is the first study demonstrating the association of inflammasome NLRP3 variants with risk and/or protection for hospitalization in COVID-19. Studies linking the NLRP3 inflammasome and SARS-CoV-2 infection are still scarce due to the recent emergence of this pathogen. Our results contribute to the discussion of the impact of inflammasomes in the clinical evolution of COVID-19.

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“…Lastly, although not a receptor involved in the phagocytosis or uptake of M.tb , multiple recent studies have examined polymorphisms in the vitamin D receptor (VDR) in different populations for their association with increased susceptibility to TB infection [ 183 , 184 , 185 , 197 ]. Other important immune factors in which SNPs have been recently studied include NLRP3 [ 186 ], AIM2 [ 179 , 187 ], and C-type lectins [ 188 , 189 ].…”

Section: Host Genetic Factorsmentioning

confidence: 99%

Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages

Simper

¹

,

Perez

²

,

Schlesinger

³

et al. 2022

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Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), is responsible for >1.5 million deaths worldwide annually. Innate immune cells, especially macrophages, are the first to encounter M.tb, and their response dictates the course of infection. During infection, macrophages exert a variety of immune factors involved in either controlling or promoting the growth of M.tb. Research on this topic has been performed in both in vitro and in vivo animal models with discrepant results in some cases based on the model of study. Herein, we review macrophage resistance and susceptibility immune factors, focusing primarily on recent advances in the field. We include macrophage cellular pathways, bioeffector proteins and molecules, cytokines and chemokines, associated microbiological factors and bacterial strains, and host genetic factors in innate immune genes. Recent advances in mechanisms underlying macrophage resistance and susceptibility factors will aid in the successful development of host-directed therapeutics, a topic emphasized throughout this review.

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Single-Nucleotide Variants in the AIM2 – Absent in Melanoma 2 Gene (rs1103577) Associated With Protection for Tuberculosis

Cited by 17 publications

References 71 publications

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

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

Nlrp3 Inflammasome Genetic Variants Are Associated With Risk And/Or Protection To Hospitalization Among Covid-19 Patients From Rio De Janeiro, Brazil

Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages

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