Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas.
Front Immunol
; 11: 550624, 2020.
Article
en En
| MEDLINE
| ID: mdl-33193317
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 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
1_ASSA2030
/
2_ODS3
/
3_ND
Problema de salud:
1_doencas_transmissiveis
/
2_enfermedades_transmissibles
/
3_neglected_diseases
/
3_tuberculosis
Asunto principal:
Tuberculosis
/
Susceptibilidad a Enfermedades
/
Interacciones Huésped-Patógeno
/
Inflamasomas
/
Mycobacterium tuberculosis
Tipo de estudio:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Risk_factors_studies
/
Screening_studies
Límite:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
País/Región como asunto:
America do sul
/
Brasil
Idioma:
En
Revista:
Front Immunol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Brasil