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

• Published in: Frontiers in immunology Vol. 11; p. 550624
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 21.10.2020
• Subjects: Adult; Alleles; Biomarkers; Brazil - epidemiology; Cohort Studies; Cytokines - metabolism; Disease Susceptibility; Female; Gene Expression Profiling; Genetic Predisposition to Disease; Genetic Variation; genetics; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Humans; Immunology; inflammasome; Inflammasomes - metabolism; Inflammation Mediators - metabolism; Male; Middle Aged; Mycobacterium tuberculosis - physiology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nlrc4; NLRP3; Patient Outcome Assessment; Polymorphism, Single Nucleotide; Population Surveillance; tuberculosis; Tuberculosis - epidemiology; Tuberculosis - etiology; Tuberculosis - metabolism; Tuberculosis - prevention & control; Virulence; Brazil; Nlrc4; NLRP3; genetics; inflammasome; tuberculosis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.550624

The interplay between (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 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. and enetic variants contribute to the presentation of TB. For the first time, we have shown that loss-of-function variants in 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.