Pulmonary Infection with Hypervirulent Mycobacteria Reveals a Crucial Role for the P2X7 Receptor in Aggressive Forms of Tuberculosis

Author(s):Show less -

Amaral, Eduardo P. ^[1] ; Ribeiro, Simone C. M. ^[2] ; Lanes, Veronica R. ^[2] ; Almeida, Fabricio M. ^[2] ; de Andrade, Marcelle R. M. ^[2] ; Barbosa Bomfim, Caio Cesar ^[1] ; Salles, Erika M. ^[1] ; Bortoluci, Karina R. ^[3] ; Coutinho-Silva, Robson ^{[4, 5]} ; Hirata, Mario H. ^[6] ; Alvarez, Jose M. ^[1] ; Lasunskaia, Elena B. ^[2] ; D'Imperio-Lima, Maria Regina ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, BR-05508 Sao Paulo - Brazil

^[2] UENF, Lab Biol Reconhecer, Rio De Janeiro - Brazil

^[3] Univ Fed Sao Paulo, Dept Ciencias Biol, Ctr Terapia Celular & Mol, Sao Paulo - Brazil

^[4] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Programa Imunobiol, BR-21941 Rio De Janeiro - Brazil

^[5] Inst Natl Ciencia & Tecnol Pesquisa Translac Saud, Rio De Janeiro - Brazil

^[6] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Quim & Toxicol Clin, BR-05508 Sao Paulo - Brazil

• Document type: Journal article
• Source: PLOS PATHOGENS; v. 10, n. 7 JUL 2014.
• Web of Science Citations: 39

Abstract

The purinergic P2X7 receptor (P2X7R) is a sensor of extracellular ATP, a damage-associated molecule that is released from necrotic cells and that induces pro-inflammatory cytokine production and cell death. To investigate whether the innate immune response to damage signals could contribute to the development of pulmonary necrotic lesions in severe forms of tuberculosis, disease progression was examined in C57BL/6 and P2X7R(-/-) mice that were intratracheally infected with highly virulent mycobacterial strains (Mycobacterium tuberculosis strain 1471 of the Beijing genotype family and Mycobacterium bovis strain MP287/03). The low-dose infection of C57BL/6 mice with bacteria of these strains caused the rapid development of extensive granulomatous pneumonia with necrotic areas, intense bacillus dissemination and anticipated animal death. In contrast, in P2X7R(-/-) mice, the lung pathology presented with moderate infiltrates of mononuclear leukocytes without visible signs of necrosis; the disease attenuation was accompanied by a delay in mortality. In vitro, the hypervirulent mycobacteria grew rapidly inside macrophages and induced death by a P2X7R-dependent mechanism that facilitated the release of bacilli. Furthermore, these bacteria were resistant to the protective mechanisms elicited in macrophages following extracellular ATP stimulation. Based on this study, we propose that the rapid intracellular growth of hypervirulent mycobacteria results in massive macrophage damage. The ATP released by damaged cells engages P2X7R and accelerates the necrotic death of infected macrophages and the release of bacilli. This vicious cycle exacerbates pneumonia and lung necrosis by promoting widespread cell destruction and bacillus dissemination. These findings suggest the use of drugs that have been designed to inhibit the P2X7R as a new therapeutic approach to treat the aggressive forms of tuberculosis. (AU)

• FAPESP's process: 10/51150-4 - Animal model for analysis of the pathogenicity of Mycobacterium bovis strains and evaluation of cellular and humoral immune responses against pathogenic isolates
• Grantee: Maria Regina D'Império Lima
• Support Opportunities: Regular Research Grants
• 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