Intervention in signaling pathways associated with cellular damage recognition to reduce the immunopathology of severe forms of tuberculosis.

Author(s)

Eduardo Pinheiro Amaral

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2015-12-02

Examining board members

Maria Regina D'Imperio Lima; Ana Paula Lepique; Paola Marcella Camargo Minoprio; Alessandra Pontillo; Ricardo Weinlich

• Advisor: Maria Regina D'Imperio Lima

Abstract

Necrosis cell death is known as an inflammatory process due to the large amount of damage signals released. During the progressive primary tuberculosis, extensive necrotic lesions in the lung and intensive bacterial dissemination are observed. In this study, we hypothesized that the amplification of pulmonary necrosis through damage signals recognition by a purinergic receptor called P2X7 (P2X7R) could favor the progression of disease, as well as the augmentation of the inflammatory response. We found that the recognition of extracellular ATP (eATP) through P2X7R is crucial to the outcome of fatal tuberculosis by favoring the induction of necrosis of infected macrophages, which facilitated the bacterial escape. The adenosine, resulted from eATP hydrolyzation, impacted to the acquired immune response activation. Our study provides a new perspective to the development of therapeutic protocols based on the inhibition of P2X7R and adenosine receptor to avoid the induction of aggressive forms of tuberculosis. (AU)

• FAPESP's process: 10/19246-1 - Role of inflammasome activation in development of the tuberculosis pathogeny induced by hypervirulent clinical isolates
• Grantee: Eduardo Pinheiro Amaral
• Support Opportunities: Scholarships in Brazil - Doctorate