Frontiers in Immunology (Oct 2020)

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

  • Dhêmerson Souza De Lima,
  • Caio C. B. Bomfim,
  • Vinícius N. C. Leal,
  • Edione C. Reis,
  • Jaíne L. S. Soares,
  • Fernanda P. Fernandes,
  • Eduardo P. Amaral,
  • Flavio V. Loures,
  • Mauricio M. Ogusku,
  • Maria R. D'Imperio Lima,
  • Aya Sadahiro,
  • Alessandra Pontillo

DOI
https://doi.org/10.3389/fimmu.2020.550624
Journal volume & issue
Vol. 11

Abstract

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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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