title: Pulmonary infection with hypervirulent Mycobacteria reveals a crucial role for the P2X7 receptor in aggressive forms of tuberculosis.
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.
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, São Paulo, Brazil.
authors.forename: Eduardo P
authors.initials: EP
authors.lastname: Amaral
authors.affiliation: Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense (UENF), Campos dos Goytacazes, Rio de Janeiro, Brazil.
authors.forename: Simone C M
authors.initials: SC
authors.lastname: Ribeiro
authors.affiliation: Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense (UENF), Campos dos Goytacazes, Rio de Janeiro, Brazil.
authors.forename: Verônica R
authors.initials: VR
authors.lastname: Lanes
authors.affiliation: Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense (UENF), Campos dos Goytacazes, Rio de Janeiro, Brazil.
authors.forename: Fabrício M
authors.initials: FM
authors.lastname: Almeida
authors.affiliation: Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense (UENF), Campos dos Goytacazes, Rio de Janeiro, Brazil.
authors.forename: Marcelle R M
authors.initials: MR
authors.lastname: de Andrade
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, São Paulo, Brazil.
authors.forename: Caio Cesar Barbosa
authors.initials: CC
authors.lastname: Bomfim
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, São Paulo, Brazil.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Salles
authors.affiliation: Centro de Terapia Celular e Molecular, Departamento de Ciências Biológicas, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Karina R
authors.initials: KR
authors.lastname: Bortoluci
authors.affiliation: Programa de Imunobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil; Instituto National de Ciência e Tecnologia para Pesquisa Translacional em Saúde e Meio Ambiente da Região Amazônica, Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Robson
authors.initials: R
authors.lastname: Coutinho-Silva
authors.affiliation: Departamento de Química e Toxicologia Clínica, Faculdade de Ciências Farmacêuticas (FCT), University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Mario H
authors.initials: MH
authors.lastname: Hirata
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, São Paulo, Brazil.
authors.forename: José M
authors.initials: JM
authors.lastname: Alvarez
authors.affiliation: Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense (UENF), Campos dos Goytacazes, Rio de Janeiro, Brazil.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Lasunskaia
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas (ICB), Universidade de São Paulo (USP), São Paulo, São Paulo, Brazil.
authors.forename: Maria Regina
authors.initials: MR
authors.lastname: D'Império-Lima
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology; D000818:Animals; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate