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Doctoral Thesis
DOI
10.11606/T.42.2016.tde-14042016-104430
Document
Author
Full name
Eduardo Pinheiro Amaral
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Lima, Maria Regina D'Imperio (President)
Lepique, Ana Paula
Minoprio, Paola Marcella Camargo
Pontillo, Alessandra
Weinlich, Ricardo
Title in Portuguese
Intervenção em vias de sinalização associadas ao reconhecimento de dano celular visando reduzir a imunopatologia das formas graves de tuberculose.
Keywords in Portuguese
Adenosina
ATP
Inflamassoma
Necrose
P2X7R
Tuberculose
Abstract in Portuguese
A morte celular necrótica é conhecida pelo seu caráter inflamatório, conferido pela grande quantidade de sinais de dano liberados. Durante a tuberculose primária progressiva é observada intensa lesão necrótica nos pulmões e disseminação do bacilo para outros órgãos. Neste estudo, nós hipotetizamos que a amplificação da necrose pulmonar, via reconhecimento de sinais de dano tecidual pelo receptor purinérgico P2X7 (P2X7R), poderia favorecer a progressão da doença, bem como a potencialização da resposta inflamatória. Vimos que o reconhecimento de extracelular ATP (eATP) via o receptor P2X7 é de suma importância para o desenvolvimento da doença grave, por favorecer a indução de necrose dos macrófagos infectados, o que facilitou o escape do bacilo. A adenosina, resultante da hidrólise do eATP, impactou na ativação da resposta imune adquirida. Nosso estudo provê uma nova perspectiva para o desenvolvimento de protocolos terapêuticos baseados na inibição do P2X7R e dos receptores de adenosina para evitar a indução de formas graves da doença.
Title in English
Intervention in signaling pathways associated with cellular damage recognition to reduce the immunopathology of severe forms of tuberculosis.
Keywords in English
Adenosine
ATP
Inflammasome
Necrosis
P2X7R
Tuberculosis
Abstract in English
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.
 
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Release Date
2020-04-14
Publishing Date
2016-04-14
 
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