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

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.550624

DOI=10.3389/fimmu.2020.550624

ISSN=1664-3224

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 NLRP3 gene (found in 30% of world population) confers protection against the development of TB, indicating a prominent role of NLRP3 inflammasome against Mtb. Through genotype-guided assays and various Mtb strains (BCG, H37Rv, Beijing-1471, MP287/03), we demonstrated that Mtb strains activate inflammasome according to NLRP3/IL-1ß or NLRC4/IL18 preferential axis. NLRP3 and NLRC4 genetic variants contribute to TB presentation. For the first time we reported 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 “house contacts” (CNT) revealed that plasma IL-1ß/IFN-α ratio lets us distinguish patients from Mtb-exposed-but-healthy individuals from endemic region. Moreover NLRP3 inflammasome resulted “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 entity of inflammasome activation contribute to susceptible/resistant profile of Mtb-exposed individuals.