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

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 develop...

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Published inFrontiers 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
LanguageEnglish
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
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Abstract 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.
AbstractList 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.
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 g enetic 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.
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.
Author Ogusku, Mauricio M
Fernandes, Fernanda P
Amaral, Eduardo P
Leal, Vinícius N C
Sadahiro, Aya
Pontillo, Alessandra
Lima, Maria R D'Imperio
Bomfim, Caio C B
Loures, Flavio V
Soares, Jaíne L S
Souza De Lima, Dhêmerson
Reis, Edione C
AuthorAffiliation 1 Laboratório de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo , São Paulo , Brazil
4 Laboratório de Micobacteriologia, Instituto Nacional de Pesquisas da Amazônia , Manaus , Brazil
5 Departamento de Parasitologia, Universidade Federal do Amazonas , Manaus , Brazil
3 Instituto de Ciência e Tecnologia, Universidade Federal de São Paulo , São José dos Campos , Brazil
2 Laboratório de Imunologia das Doenças Infecciosas, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo , São Paulo , Brazil
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– name: 1 Laboratório de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo , São Paulo , Brazil
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  givenname: Alessandra
  surname: Pontillo
  fullname: Pontillo, Alessandra
  organization: Laboratório de Imunogenética, Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
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Copyright Copyright © 2020 Souza De Lima, Bomfim, Leal, Reis, Soares, Fernandes, Amaral, Loures, Ogusku, Lima, Sadahiro and Pontillo.
Copyright © 2020 Souza De Lima, Bomfim, Leal, Reis, Soares, Fernandes, Amaral, Loures, Ogusku, Lima, Sadahiro and Pontillo. 2020 Souza De Lima, Bomfim, Leal, Reis, Soares, Fernandes, Amaral, Loures, Ogusku, Lima, Sadahiro and Pontillo
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Keywords Nlrc4
NLRP3
genetics
inflammasome
tuberculosis
Language English
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Reviewed by: Andre G. Loxton, South African Medical Research Council, South Africa; Claudia A. S. Lage, Federal University of Rio de Janeiro, Brazil
This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology
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Snippet The interplay between (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis (TB) still...
The interplay between M. tuberculosis (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis...
The interplay between M. tuberculosis (Mtb) and humans is multifactorial. The susceptibility/resistance profile and the establishment of clinical tuberculosis...
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StartPage 550624
SubjectTerms 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
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Title Combining Host Genetics and Functional Analysis to Depict Inflammasome Contribution in Tuberculosis Susceptibility and Outcome in Endemic Areas
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