Evaluation of the role of P2X7 receptor for pulmonary macrophage activation and cell death during aggressive forms of Tuberculosis.

• Grant number: 15/19126-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2016
• End date: August 09, 2016
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Eduardo Pinheiro Amaral
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Tuberculosis remains an emergent problem of public health. Over the years, the mycobacteria have acquired mutations able to modify their virulence and/or resistance to chemotherapy. In previous studies, we published that in contrast to the most common laboratory Mycobacterium tuberculosis (Mtb) complex isolates, hypervirulent isolates display a unique ability to modulate the immune response in murine experimental models. In particular, we showed that the purinergic receptor P2X7, which recognizes extracellular ATP released during necrotic cell death, is crucial for the fatal outcome of the disease only in response to hypervirulent Mtb infection. However, the exact mechanism in which P2X7R-mediated necrosis macrophage death is induced in the lung during severe TB is still unclear. Thus, we here propose to investigate in more details the role of P2X7R in the activation and cell death modulation of the pulmonary macrophages during infection by hypervirulent mycobacteria. For that, we here propose to perform of series of Mtb infection experiments involving mice deficient in P2X7R, required for necrosis modulation, as well as, treating infected animals with drugs known to inhibit purinergic signaling in vivo. The present work will improve the understanding about the cellular and molecular mechanisms underlying the pulmonary necrosis during disease induced by hypervirulent mycobacteria and may open new perspectives to develop adjunctive therapeutic approaches to subvert necrotic cell death, thereby preventing the fatal outcome of aggressive TB.

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.; 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)