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

Frontiers in Immunology
D Souza de LimaA Pontillo

Abstract

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 t...Continue Reading

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Citations

Apr 20, 2021·Frontiers in Immunology·Mariana Brasil de Andrade FigueiraAya Sadahiro
Aug 8, 2021·Microbial Pathogenesis·Dhêmerson Souza de LimaAntonio Luiz Boechat

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Methods Mentioned

BETA
Assay
Genotyping
density gradient centrifugation
flow cytometry
ELISA
fluorescence microscopy
flow-cytometry

Software Mentioned

QuantStudio
GraphPad Prism
project
R
SNPassoc

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