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

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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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 11, OCT 21 2020.
• Citações Web of Science: 0

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-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)

• Processo FAPESP: 15/20432-8 - Intervenção em vias de sinalização associadas ao reconhecimento de dano celular visando reduzir a patologia das formas graves de malária e tuberculose
• Beneficiário: Maria Regina D'Império Lima
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 15/23395-6 - Imunogenetica do inflamassoma, estudo translacional "da clinica a bancada,da bancada a clinica":analise das variações nos genes do inflamassoma em doenças autoinflamatorias monogênicas e multifatoriais para diagnostico diferencial e aplicações terapêutica
• Beneficiário: Alessandra Pontillo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/50650-7 - Caracterização de novos alvos moleculares no controle da obesidade e da inflamação induzida pela obesidade
• Beneficiário: Alessandra Pontillo
• Modalidade de apoio: Auxílio à Pesquisa - Regular