Evaluation of the involvement of lysosomal cathepsins in the NLRP3-inflammasome activation induced by recombinant ESAT-6 from Mycobacterium tuberculosis

• Grant number: 13/07298-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): September 02, 2013
• Effective date (End): July 01, 2014
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Eduardo Pinheiro Amaral
• Supervisor: Franklin Alan Sher
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: National Institutes of Health, Bethesda (NIH), United States
• Associated to the scholarship: 10/19246-1 - Role of inflammasome activation in development of the tuberculosis pathogeny induced by hypervirulent clinical isolates, BP.DR

Abstract

Tuberculosis remains an emergent problem of public health. Over the years, the mycobacteria have acquired genetic mutations, which is responsible for virulence increase virulence and/or resistance to chemotherapy. Previously, we observed that hypervirulent isolates from Mtb complex have different ability to modulate the immune response in murine experimental model. We also observed that the immune response activation, characterized by a very low production of inflammatory mediators and an increase of IL-10 production, or, on the other hand, characterized by increase production of IL-1b, NO and IFN-g, may reduce mice survival. Recently, has been reported that mycobacteria are capable of inducing inflammatory response through inflammasomes activation, which resulted in IL-1b production. It also was demonstrated that IL-1b, IL-1bR and caspase-1 deficient mice infected with Mtb (H37Rv) had low survival, suggesting that IL-1b production is crucial for control of the infection. As aim of PhD project (Project number 2010/19246-1) we propose to investigate the role of NLRP3-inflammasome activation in the development of severe tuberculosis. Thus, we have been shown that a damage signal released during induction of necrotic cell death, for example ATP, is very important to induction of severe disease. As known, extracellular ATP (eATP) can be recognized by P2X7 receptor and promotes the activation of NLRP3/ASC/Caspase-1 complex. Our previous data suggest that the activation of P2X7 receptor is important to induction of severe tuberculosis and the axis NLRP3/ASC/Caspase-1 and P2X7R contribute to regulation of IL-1b secreation. However, the molecular mechanisms involved in the NLRP3-inflammasome activation require elucidation proposed in this BEPE project. (AU)

Scientific publications

(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)

AMARAL, EDUARDO P.; RITEAU, NICOLAS; MOAYERI, MAHTAB; MAIER, NOLAN; MAYER-BARBER, KATRIN D.; PEREIRA, ROSANA M.; LAGE, SILVIA L.; KUBLER, ANDRE; BISHAI, WILLIAM R.; D'IMPERIO-LIMA, MARIA R.; et al. Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages. FRONTIERS IN IMMUNOLOGY, v. 9, JUN 21 2018. (13/07298-5)

AMARAL, EDUARDO P.; CONCEICAO, ELISABETE L.; COSTA, DIEGO L.; ROCHA, MICHAEL S.; MARINHO, JAMOCYR M.; CORDEIRO-SANTOS, MARCELO; D'IMPERIO-LIMA, MARIA REGINA; BARBOSA, THEOLIS; SHER, ALAN; ANDRADE, BRUNO B.. N-acetyl-cysteine exhibits potent anti-mycobacterial activity in addition to its known anti-oxidative functions. BMC Microbiology, v. 16, OCT 28 2016. (13/07298-5, 10/51150-4, 15/19126-0)