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

• DOI: 10.1371/journal.ppat.1004188
• Publication Date: 2014-07-03T18:09:47Z
• Authors: Eduardo P. Amaral; Simone C. M. Ribeiro; Verônica R. Lanes; Fabrício M. Almeida; Marcelle R. M. de...; Caio Cesar Barbos...; Érika M. Salles; Karina R. Bortoluci; Robson Coutinho-S...; Mario H. Hirata; José M. Alvarez; Elena B. Lasunskaia; Maria Regina D'Im...
• Keywords: Mice, Knockout; 0303 health sciences; QH301-705.5; Macrophages; Mycobacterium tuberculosis; RC581-607; Mycobacterium bovis; 3. Good health; Mice; 03 medical and health sciences; Adenosine Triphosphate; Animals; Humans; Receptors, Purinergic P2X7; Immunologic diseases. Allergy; Biology (General); Tuberculosis, Pulmonary; Research Article

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