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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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De Lima, Dhemerson Souza [1] ; Bomfim, Caio C. B. [2] ; Leal, Vinicius N. C. [1] ; Reis, Edione C. [1] ; Soares, Jaine L. S. [1] ; Fernandes, Fernanda P. [1] ; Amaral, Eduardo P. [2] ; Loures, V, Flavio ; Ogusku, Mauricio M. [3] ; D'Imperio Lima, Maria R. [2] ; Sadahiro, Aya [4] ; Pontillo, Alessandra [1]
Total Authors: 12
Affiliation:
[1] Univ Sao Paulo, Dept Imunol, Inst Ciencias Biomed, Lab Imunogenet, Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Lab Imunol Doencas Infecciosas, Sao Paulo - Brazil
[3] Inst Nacl de Pesquisas da Amazonia, Lab Micobacteriol, Manaus, Amazonas - Brazil
[4] Univ Fed Amazonas, Dept Parasitol, Manaus, Amazonas - Brazil
Total Affiliations: 4
Document type: Journal article
Source: FRONTIERS IN IMMUNOLOGY; v. 11, OCT 21 2020.
Web of Science Citations: 0
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-alpha 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. (AU)

FAPESP's process: 15/20432-8 - Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis
Grantee:Maria Regina D'Império Lima
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 15/23395-6 - Immunogenetics of the inflammasome and translational study "from bed to bench and back": analysis of variations in inflammasome genes in monogenic and multifactorial autoinflammatory diseases for differential diagnosis and therapeutic applications
Grantee:Alessandra Pontillo
Support Opportunities: Regular Research Grants
FAPESP's process: 15/50650-7 - Characterization of novel molecular players in the control of obesity and obesity-induced inflammation
Grantee:Alessandra Pontillo
Support Opportunities: Regular Research Grants