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

2020; Frontiers Media; Volume: 11; Linguagem: Inglês

10.3389/fimmu.2020.550624

1664-3224

Dhêmerson Souza de Lima, Caio César Barbosa Bomfim, Vinícius Nunes Cordeiro Leal, Edione C. Reis, Jaíne L. S. Soares, Fernanda Pereira Fernandes, Eduardo P. Amaral, Flávio V. Loures, Maurício Morishi Ogusku, Maria Regina D’Império Lima, Aya Sadahiro, Alessandra Pontillo,

interferon and immune responses

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.