Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis

Lima, Dhêmerson Souza de; Ogusku, Maurício Morishi; Sadahiro, Aya; Pontillo, Alessandra

doi:10.1016/j.meegid.2016.04.015

Cited by 26 publications

(23 citation statements)

References 42 publications

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“…The ClinVar database describes no common CARD8 genetic variants or confirmed functional variants. In the literature, several CARD8 SNPs were investigated in only one study, while rs6509365 was evaluated more frequently [21][22][23][24][25]. This intron variant was associated with melanoma and susceptibility to tuberculosis [21,23,25].…”

Section: Discussionmentioning

confidence: 99%

Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome

et al. 2020

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Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder of multifactorial etiopathology likely to involve the interactions between genetics and lifestyle. Chronic inflammation and oxidative stress (OS) may participate in the pathophysiology of the syndrome. The question of the extent to which OS and inflammation are causally related to the development of the syndrome and metabolic complications remains unanswered. By our knowledge, the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome as an important trigger of inflammatory pathways and NLRP3 and CARD8 polymorphisms has never been addressed in PCOS yet. We conducted a case-control study conducting of total 169 Slovenian PCOS patients and 83 healthy blood donors. They were genotyped for polymorphisms in antioxidative (SOD2 rs4880, CAT rs1001179, PON1 rs854560, and rs662) and inflammatory pathways genes (NLRP3 rs35829419, CARD8 rs2043211, TNF rs1800629, IL1B rs1143623, and rs16944, IL6 rs1800795) using competitive allele-specific polymerase chain reaction (PCR). Logistic regression and the Mann–Whitney test were used in the statistical analysis. SOD2 rs4880, CARD8 rs2043211, and IL1B rs16944 were associated with the risk of developing PCOS. Furthermore, the interactions between CARD8 rs2043211 and IL6 rs1800795 and between IL1B rs1143623 and IL6 rs1800795 also significantly affected the risk for PCOS. With regard to glucose homeostasis, CAT rs1001179, SOD2 rs4880, PON1 rs854560, NLRP3 rs35829419, and TNF rs1800629 were significantly associated with response to the glycemic load. Our data indicate that the genetic variability in the antioxidative and inflammatory pathways influences the development of PCOS and glucose homeostasis in PCOS patients.

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Section: Discussionmentioning

confidence: 99%

Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome

et al. 2020

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“…For TB evidence for both, a protective role of NLRP3 and IL-1β, as well as a pathogenic immune reaction can be found: Mice defective of IL-1β are more susceptible for TB [53] and human macrophages isolated from three individuals with combined gain-of-function-mutations of NLRP3 (rs35829419, M299V-no assigned rs number yet) and Card8 (rs2043211) in vitro allow a decreased mycobacterial growth and higher levels of IL-1β [54]. Further, SNP analysis revealed that a mutation leading to higher cytosolic activity of NLRP3 (rs10754558) protects from PTB in a Brazilian cohort [55], which similarly has been linked to HIV and HTVL-1 infection. In contrast, a recent investigation of these SNPs in a large Ethiopian cohort has found some evidence for an association with poor clinical outcome of PTB [56] and it has also been associated with early mortality in HIV/TB co-infection in Botswana.…”

Section: Nlrp3-the Cytosolic Multisensormentioning

confidence: 95%

RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies

Burkert

Schumann

2020

Vaccines

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Tuberculosis (TB) is still an important global threat and although the causing organism has been discovered long ago, effective prevention strategies are lacking. Mycobacterium tuberculosis (MTB) is a unique pathogen with a complex host interaction. Understanding the immune responses upon infection with MTB is crucial for the development of new vaccination strategies and therapeutic targets for TB. Recently, it has been proposed that sensing bacterial nucleic acid in antigen-presenting cells via intracellular pattern recognition receptors (PRRs) is a central mechanism for initiating an effective host immune response. Here, we summarize key findings of the impact of mycobacterial RNA sensing for innate and adaptive host immunity after MTB infection, with emphasis on endosomal toll-like receptors (TLRs) and cytosolic sensors such as NLRP3 and RLRs, modulating T-cell differentiation through IL-12, IL-21, and type I interferons. Ultimately, these immunological pathways may impact immune memory and TB vaccine efficacy. The novel findings described here may change our current understanding of the host response to MTB and potentially impact clinical research, as well as future vaccination design. In this review, the current state of the art is summarized, and an outlook is given on how progress can be made.

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“…As our previous results pointed out the protective role of a gain-of-function genetic variant in NLRP3 (rs10754558) (18), and given the central role of this receptor in the mouse model of Mtb infection as well (10-12), we next asked whether the observed activation of inflammasome complex by Mtb H37Rv in MDM could be dependent on NLRP3. The formation of specks indicates the activation of inflammasome and also allows for the visualization of a mounted complex platform, including the activated sensor (26).…”

Section: Nlrp3 Contributes To Inflammasome Activation By the Mtb Commmentioning

confidence: 99%

“…We previously reported the protective gain-of-function effect of a Single Nucleotide Variant (SNV) in the NLRP3 3'UTR region (rs10754558; found in about 30% of the world population) against the development of pulmonary TB (18). This led us to hypothesize genes coding factors taking part in the inflammasome assembling and function, which directly influences the IL-1ß and/or IL-18 production, could affect the outcome of an Mtb infection, therefore determining either the susceptibility and/or the prognosis for a TB patients.…”

Section: Introductionmentioning

confidence: 99%

Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas

et al. 2020

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The interplay between M. tuberculosis (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis (TB) still remains elusive. The gain-of-function variant rs10754558 in the NLRP3 gene (found in 30% of the world population) confers protection against the development of TB, indicating a prominent role played by NLRP3 inflammasome against Mtb. Through genotype-guided assays and various Mtb strains (BCG, H37Rv, Beijing-1471, MP287/03), we demonstrate that Mtb strains activate inflammasome according to the NLRP3/IL-1ß or NLRC4/IL18 preferential axis. NLRP3 and NLRC4 genetic variants contribute to the presentation of TB. For the first time, we have shown that loss-of-function variants in NLRC4 significantly contribute to the development of extra-pulmonary TB. The analysis of inflammasome activation in a cohort of TB patients and their "household contacts" (CNT) revealed that plasma IL-1ß/IFN-α ratio lets us distinguish patients from Mtb-exposed-but-healthy individuals from an endemic region. Moreover, NLRP3 inflammasome seemed "exhausted" in TB patients compared to CNT, indicating a more efficient activation of inflammasome in resistant individuals. These findings suggest that inflammasome genetics as well as virulence-dependent level of inflammasome activation contribute to the onset of a susceptible/resistant profile among Mtb-exposed individuals.

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Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis

Cited by 26 publications

References 42 publications

Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome

Genetic Variability in Antioxidative and Inflammatory Pathways Modifies the Risk for PCOS and Influences Metabolic Profile of the Syndrome

RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies

Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas

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