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.
Highlights
Tuberculosis (TB) is a serious public health issue, with nearly 9 million new annual cases of the disease worldwide and 1.3 million deaths per year [1]
We focused our study on the purinergic P2X7 receptor (P2X7R), a sensor of adenosine triphosphate (ATP) that is released from necrotic cells and that induces pro-inflammatory cytokine production and cell death
Because ATP released from necrotic cells activates P2X7R and subsequently the innate immune response [23,26,27], we wondered if this molecular pathway may contribute to the development of the aggressive forms of TB that are associated with intense pulmonary necrosis
Summary
Tuberculosis (TB) is a serious public health issue, with nearly 9 million new annual cases of the disease worldwide and 1.3 million deaths per year [1]. Mycobacteria are typically transmitted by aerosols and reach the lungs, where macrophages and other immune cells are recruited during the early innate response to infection. The latent infection results from the equilibrium between mycobacteria and the host defenses, in which inflammatory cells become organized as primary granulomas. The reactivation of latent infections in immunocompetent individuals occurs at rates that range from 3% to 10% per lifespan [3]; these rates are dramatically increased by co-infection with the human immunodeficiency virus (HIV) [4]. Accelerations in active TB reactivations have been described after the administration of tumor necrosis factor (TNF)a/IL-12/IL-23 blockers, which are used to treat inflammatory diseases, such as rheumatoid arthritis
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