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

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dc.contributor.authorAmaral, Eduardo P.
dc.contributor.authorRibeiro, Simone C. M.
dc.contributor.authorLanes, Veronica R.
dc.contributor.authorAlmeida, Fabricio M.
dc.contributor.authorAndrade, Marcelle R. M. de
dc.contributor.authorBarbosa Bomfim, Caio Cesar
dc.contributor.authorSalles, Erika M.
dc.contributor.authorBortoluci, Karina R. [UNIFESP]
dc.contributor.authorCoutinho-Silva, Robson
dc.contributor.authorHirata, Mario H.
dc.contributor.authorAlvarez, Jose M.
dc.contributor.authorLasunskaia, Elena B.
dc.contributor.authorD'Imperio-Lima, Maria Regina
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUENF
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniversidade Federal do Rio de Janeiro (UFRJ)
dc.contributor.institutionInst Natl Ciencia & Tecnol Pesquisa Translac Saud
dc.date.accessioned2016-01-24T14:37:29Z
dc.date.available2016-01-24T14:37:29Z
dc.date.issued2014-07-01
dc.description.abstractThe 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.en
dc.description.affiliationUniv São Paulo, Inst Ciencias Biomed, Dept Imunol, BR-05508 São Paulo, Brazil
dc.description.affiliationUENF, Lab Biol Reconhecer, Rio de Janeiro, Brazil
dc.description.affiliationUniversidade Federal de São Paulo, Dept Ciencias Biol, Ctr Terapia Celular & Mol, São Paulo, Brazil
dc.description.affiliationUniv Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Programa Imunobiol, BR-21941 Rio de Janeiro, Brazil
dc.description.affiliationInst Natl Ciencia & Tecnol Pesquisa Translac Saud, Rio de Janeiro, Brazil
dc.description.affiliationUniv São Paulo, Fac Ciencias Farmaceut, Dept Quim & Toxicol Clin, BR-05508 São Paulo, Brazil
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Ciencias Biol, Ctr Terapia Celular & Mol, São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
dc.description.sponsorshipIDFAPESP: 2010/51150-4
dc.description.sponsorshipIDCNPq: 471869/2010-4
dc.description.sponsorshipIDCNPq: 473453/2011-8
dc.description.sponsorshipIDFAPERJ: E-26/110.623/2011
dc.description.sponsorshipIDCNPq: 25/2006
dc.description.sponsorshipIDFAPESP: 2010/19246-1
dc.format.extent14
dc.identifierhttp://dx.doi.org/10.1371/journal.ppat.1004188
dc.identifier.citationPlos Pathogens. San Francisco: Public Library Science, v. 10, n. 7, 14 p., 2014.
dc.identifier.doi10.1371/journal.ppat.1004188
dc.identifier.fileWOS000340551000009.pdf
dc.identifier.issn1553-7366
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/37904
dc.identifier.wosWOS:000340551000009
dc.language.isoeng
dc.publisherPublic Library Science
dc.relation.ispartofPlos Pathogens
dc.rightsinfo:eu-repo/semantics/openAccess
dc.titlePulmonary Infection with Hypervirulent Mycobacteria Reveals a Crucial Role for the P2X7 Receptor in Aggressive Forms of Tuberculosisen
dc.typeinfo:eu-repo/semantics/article
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