RESUMO
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.
Assuntos
Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/metabolismo , Mycobacterium tuberculosis/fisiologia , Tuberculose/etiologia , Tuberculose/metabolismo , Adulto , Alelos , Biomarcadores , Brasil/epidemiologia , Estudos de Coortes , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Avaliação de Resultados da Assistência ao Paciente , Polimorfismo de Nucleotídeo Único , Vigilância da População , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , VirulênciaRESUMO
Siglec-1/CD169 is a sialoadhesin expressed by macrophages thought to function in cell-to-cell interactions. In the lung, the expression of Siglec-1 is specific for alveolar macrophages and single nucleotide polymorphisms (SNPs) in SIGLEC1 have been recently associated with asthma severity. Taking in account the role of alveolar macrophages in the control of M. tuberculosis and the poor literature about the contribution of SIGLEC1 genetics in M. tuberculosis susceptibility and development of pulmonary active TB, selected SNPs in SIGLEC1 were analysed in a case/control cohort from a TB endemic area of Brazil Amazon. Our findings evidenced for the first time the novel association between SIGLEC1 rs3859664 SNP and active pulmonary TB. Intriguingly, carriers of the polymorphism produced less IL-1ß than non-carriers, suggesting the possible involvement of Siglec-1 signalling pathway with inflammasome complex.