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Role of inflammasomas in the pathogenesis of tuberculosis caused by hypervirulent clinical isolates of mycobacteria

Grant number: 13/07140-2
Support Opportunities:Regular Research Grants
Duration: April 01, 2014 - March 31, 2016
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal Investigator:Maria Regina D'Império Lima
Grantee:Maria Regina D'Império Lima
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Tuberculosis remains a major public health problem. One third of the world population is infected with mycobacteria of the Mycobacterium tuberculosis complex (Mycobacterium tuberculosis - Mtb and Mycobacterium bovis - Mbv) and 10% of these individuals will develop the disease throughout their lives. Gene mutations are responsible for the increased virulence of these mycobacteria and/or resistance to chemotherapeutic agents used to treat tuberculosis. It has been reported that Mtb induces the inflammatory response via activation of inflamasomes, culminating in the secretion of IL-1². Mice deficient in IL-1², IL-1²R or caspase-1 infected with Mtb show high mortality compared to wild-type animals. These data suggest that IL-1², largely produced through inflammasome activation, is important for host survival. However, most of these studies were performed with the virulent H37Rv Mtb strain, which is considered a reference for the study of tuberculosis but does not reflect the diversity of microorganisms in nature. Statement of problem: In a previous study, we observed that mice infected with hypervirulent mycobacterial isolates have extreme behaviors regarding the ability to modulate the immune response. In some cases (i.e. MP287/03 Mbv), there is a deficient activation of the immune response with low productions of the proinflammatory mediators IL-1², IL-6, IL-17, TNF-±, IFN-³ and nitric oxide and high production of the regulatory cytokine IL-10 in the lungs. In other cases (i.e. Beijing 1471 Mtb), there is an exacerbated production of proinflammatory mediators, which appear to contribute to delay the death of mice. We also found that the profile of in vivo immune responses directly correlates with the level of in vitro IL-1² production by macrophages, suggesting that these bacteria activate differently the inflammasomes.Experimental strategy: In view of these considerations, we intend to investigate the role of inflammasomes in the pathogenesis of tuberculosis caused by hypervirulent clinical isolates (MP287/03 Mbv and Beijing 1471 Mtb), in comparison with the reference virulent strain of H37Rv Mtb. Using C57BL/6 mice and mice deficient in PYCARD/ASC, caspase-1, NLRP3, NLRC4 and P2X7, we will analyze: 1) The involvement of inflammasomes in the activation and death of infected macrophages; 2) The impact of inflammasome signaling in protection and pathogenesis of the disease; 3) The role of inflammasome activation in the development of acquired immune response; 4) The participation of purinergic P2X7 receptor in the activation of inflammasomes and its consequences.Expected results: To determine how hypervirulent mycobacteria differently modulate the activation of inflammasomes and, in consequence, the production of proinflammatory mediators.Expected contribution to the field: To provide the theoretical framework to understand the mechanisms involved in the pathogenicity of hypervirulent mycobacterial isolates, opening the possibility that in the future we can modify the course of severe forms of tuberculosis.Existing support: This study is fully consistent with the work being developed in our research group with the support of FAPESP (masters, doctoral and postdoctoral fellowships), CNPq (productivity and postdoctoral fellowships) and USP (core research support). (AU)

Articles published in Pesquisa FAPESP Magazine about the research grant:
A very aggressive bacillus 
Un bacilo muy agresivo 
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Scientific publications (9)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DA SILVA, HENRIQUE BORGES; FONSECA, RAISSA; PEREIRA, ROSANA MOREIRA; CASSADO, ALEXANDRA DOS ANJOS; ALVAREZ, JOSE MARIA; D'IMPERIO LIMA, MARIA REGINA. Splenic macrophage subsets and their function during blood-borne infections. FRONTIERS IN IMMUNOLOGY, v. 6, . (13/07140-2, 14/00810-5)
BARBOSA BOMFIM, CAIO CESAR; AMARAL, EDUARDO PINHEIRO; CASSADO, ALEXANDRA DOS ANJOS; SALLES, ERIKA MACHADO; DO NASCIMENTO, ROGERIO SILVA; LASUNSKAIA, ELENA; HIRATA, MARIO HIROYUKI; ALVAREZ, JOSE MARIA; D'IMPERIO-LIMA, MARIA REGINA. P2X7 receptor in Bone Marrow-Derived cells aggravates Tuberculosis caused by hypervirulent Mycobacterium bovis. FRONTIERS IN IMMUNOLOGY, v. 8, . (13/07140-2, 15/20432-8, 12/22587-0, 14/22986-8)
AMARAL, EDUARDO P.; LASUNSKAIA, ELENA B.; D'IMPERIO-LIMA, MARIA REGINA. Innate immunity in tuberculosis: how the sensing of mycobacteria and tissue damage modulates macrophage death. Microbes and Infection, v. 18, n. 1, p. 11-20, . (13/07140-2, 10/19246-1)
CASSADO, ALEXANDRA DOS ANJOS; D'IMPERIO LIMA, MARIA REGINA; BORTOLUCI, KARINA RAMALHO. Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. FRONTIERS IN IMMUNOLOGY, v. 6, . (13/07140-2, 13/16010-5)
DE MENEZES, MARIA NOGUEIRA; SALLES, ERIKA MACHADO; VIEIRA, FLAVIA; AMARAL, EDUARDO PINHEIRO; ZUZARTE-LUIS, VANESSA; CASSADO, ALEXANDRA; EPIPHANIO, SABRINA; ALVAREZ, JOSE MARIA; ALVES-FILHO, JOSE CARLOS; MOTA, MARIA MANUEL; et al. IL-1 alpha, promotes liver inflammation and necrosis during blood-stage Plasmodium chabaudi malaria. SCIENTIFIC REPORTS, v. 9, . (15/20432-8, 13/09176-4, 13/07140-2, 15/25874-9)
DA SILVA, HENRIQUE BORGES; DE SALLES, ERIKA MACHADO; LIMA-MAURO, ELIANA FAQUIM; SARDINHA, LUIZ ROBERTO; ALVAREZ, JOSE MARIA; D'IMPERIO LIMA, MARIA REGINA. CD28 deficiency leads to accumulation of germinal-center independent IgM(+) experienced B cells and to production of protective IgM during experimental malaria. PLoS One, v. 13, n. 8, . (13/07140-2, 15/20432-8, 09/08559-1, 10/51150-4)
DE SALLES, ERIKA MACHADO; DE MENEZES, MARIA NOGUEIRA; SIQUEIRA, RENAN; DA SILVA, HENRIQUE BORGES; AMARAL, EDUARDO PINHEIRO; CASTILLO-MENDEZ, SHEYLA INES; CUNHA, ISABELA; CASSADO, ALEXANDRA DOS ANJOS; VIEIRA, FLAVIA SARMENTO; NICHOLAS OLIVIERI, DAVID; et al. P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria. PLOS PATHOGENS, v. 13, n. 8, . (13/07140-2, 15/20432-8, 10/51150-4, 11/11053-2)
DA SILVA, HENRIQUE BORGES; FONSECA, RAISSA; ALVAREZ, JOSE M.; D'IMPERIO LIMA, MARIA REGINA. IFN-gamma Priming Effects on the Maintenance of Effector Memory CD4(+) T Cells and on Phagocyte Function: Evidences from Infectious Diseases. CLINICAL & DEVELOPMENTAL IMMUNOLOGY, . (13/07140-2, 14/00810-5)
MOREIRA, VANESSA; TEIXEIRA, CATARINA; DA SILVA, HENRIQUE BORGES; D'IMPERIO LIMA, MARIA REGINA; DOS-SANTOS, MARIA CRISTINA. The role of TLR2 in the acute inflammatory response induced by Bothrops atrox snake venom. Toxicon, v. 118, p. 121-128, . (13/07140-2, 14/00810-5, 11/21341-5)

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