Inflammasome genetic variants are associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

Abstract

BackgroundTuberculosis (TB) and AIDS are the leading causes of infectious diseases death worldwide. Here, we investigated the relationship between from single nucleotide polymorphisms (SNPs) of the NLRP3, CARD8, AIM2, CASP-1, IFI16, and IL-1β inflammasome genes, as well as the profiles of secreted proinflammatory cytokines (e.g., IL-1β, IL-18, IL-33, and IL-6) with the TB clinical profiles, TB-HIV coinfection, and IRIS onset.MethodsThe individuals were divided into four groups: TB-HIV group (n=88; 11 of them with IRIS), HIV-1 group (n=20), TB group (n=24) and healthy volunteers (HC) group (n=10), and were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. Real-time PCR was used to determine the genotypes of the Single Nucleotide Polymorphism (SNPs), and ELISA was used to measure the plasma cytokine levels. Unconditional logistic regression models were used to perform risk estimations.ResultsA higher risk for extrapulmonary TB was associated with the TT genotype (aOR=6.76; P=0.026) in the NLRP3 rs4612666 Single Nucleotide Polymorphism (SNP) and the C-C-T-G-C haplotype (aOR=4.99; P= 0.017) in the NLRP3 variants. This same Single Nucleotide Polymorphism (SNP) was associated with lower risk against extrapulmonary TB when the carrier allele C (aOR=0.15; P=0.021) was present. Among those with HIV-1 infections, a higher risk for TB onset was associated with the GA genotype (aOR=5.5; P=0.044) in the IL1-β rs1143634 Single Nucleotide Polymorphism (SNP). In contrast, lower risk against TB onset was associated with the A-G haplotype (aOR=0.17; P= 0.026) in the CARD8 variants. Higher IL-6 and IL-33 levels were observed in individuals with TB. A higher risk for IRIS onset was associated with CD8 counts ≤ 500 cells/mm3 (aOR=12.32; P=0.010), the presence of extrapulmonary TB (aOR=6.6; P=0.038), and the CT genotype (aOR=61.06; P=0.026) or carrier allele T (aOR=61.06; P=0.026) in the AIM2 rs2276405 Single Nucleotide Polymorphism (SNP), whereas lower risk against IRIS onset was associated with the AT genotype (aOR=0.02; P=0.033) or carrier allele T (aOR=0.02; P=0.029) in the CARD8 rs2043211 Single Nucleotide Polymorphism (SNP) and the T-G haplotype (aOR=0.07; P= 0.033) in the CARD8 variants. No other significant associations were observed.ConclusionsOur results depict the involvement of genetic polymorphisms of crucial innate immunity genes and proinflammatory cytokines in the clinical outcomes related to TB-HIV coinfection.

Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome—An Extempore Game of Misfiring with Defense Arsenals

“…The same group from Brazil investigated the relationship between the SNPs of inflammasome genes and the onset of TB-IRIS. The study findings reveal the association of a higher risk of IRIS with the CT genotype or carrier allele T in the AIM2 gene, thereby confirming the involvement of polymorphisms in genes belonging to the innate immunity in the onset of TB-IRIS [ 60 ]. A recent study evaluated several blood transcriptomic TB signatures as tools to predict TB-IRIS before starting ART and the diagnosis of IRIS among a HIV-infected pediatric cohort initiating ART, and they demonstrated a modest but significant prognostic and diagnostic profile [ 68 ].…”

“…Various studies have evaluated the potential role of various inflammatory cytokines and acute-phase reactants as biomarkers of TB-IRIS and the findings, though encouraging, are not concrete enough to be considered clinically useful now. Elevated levels of CRP, IL-6, IL-18, IP-10, IL-33, IFN-γ, and sCD14 individually or in combination have been investigated extensively as predictors for paradoxical TB-IRIS [ 15 , 50 , 57 , 58 , 59 , 60 ]. A prospective observational study from Botswana evaluated 26 plasma biomarkers in baseline specimens and revealed an association between TB-IRIS and lower growth factors such as IL-3, Th1 cytokine responses and low levels of IL-17 [ 16 ].…”

“…IL-18 has been suggested as the potential biomarker for predicting TB-IRIS, which highlights the important role of inflammasomes such as NLRP3 and AIM2 in the pathogenesis of TB-IRIS [ 57 , 87 , 88 ]. A recent study found, when investigating the distribution of SNPs of inflammasome genes, the proinflammatory cytokine profiles and their impact on the onset of TB-IRIS and an association between the C/T genotype and carrier-T in the AIM2 polymorphism with the increased risk of TB-IRIS [ 60 ].…”

Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome – An Extempore Game of Bursting Firecrackers with Defense Arsenals

“…extensively as predictors for paradoxical TB-IRIS. [15,[50][51][52][53][54] A prospective observational study from Botswana evaluated 26 plasma biomarkers in baseline specimens and revealed an association between TB-IRIS and lower growth factors such as IL-3, Th1 cytokine responses and low levels of IL-17. [16] A study that investigated the role of IFN-γ release assays in response to mycobacterial antigens as a diagnostic marker for TB-IRIS did not reveal any significant differences between those who developed TB-IRIS and those who did not.…”

“…The study findings reveal the association of a higher risk of IRIS with the CT genotype or carrier allele T in the AIM2 gene, thereby confirming the involvement of polymorphisms in genes belonging to the innate immunity in the onset of TB-IRIS. [54] A recently study evaluated several blood transcriptomic TB signatures as tools to predict TB-IRIS before starting ART and diagnosis of IRIS among a HIV-infected pediatric cohort initiating ART and they demonstrated a modest but significant prognostic and diagnostic profiles. [62] In a pilot metabolomic study of TB-IRIS, Silva et al found that pathways involving the participation of arachidonic acid, linoleic acid, and glycerophospholipid metabolism are relevant markers in patients who are at increased risk of developing TB-…”