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.

Population genomics ofMycobacterium tuberculosisin the Inuit

“…For instance, the polyketide synthase-derived phenolic glycolipid (PGL) coded by the intact pks15/1 locus of strain HN878 (Beijing genotype) induces hyperlethality in murine disease models (26), potentially explaining the emergence of the Beijing strain in a number of settings worldwide (27). Furthermore, compared with other clinical strains, strains 1471 and HN878 (Beijing genotypes) result in increased macrophage necrosis (28) and more progressive pathology in experimental infections (29). However, although certain strains have a propensity to cause accelerated life-threatening pathology in experimental models, it is not yet clear whether this property predicts epidemiologic success, as a strain that causes chronic, nonprogressive pathology may be the most likely to transmit.…”

The role of the P2X7 receptor in murine cutaneous leishmaniasis: aspects of inflammation and parasite control

“…*p < 0.05; **p < 0.01 using Student's t test and one-way ANOVA coupled to Tukey's post hoc test comparing infected P2X7 KO and WT mice at the same timepoint [13,24,25]. The role of the P2X7 receptor in a wide range of infectious diseases has been studied in vitro and in vivo using P2X7 KO mice [10,26,27]. The P2X7 receptor appears to be crucial during the immunological response against M. tuberculosis because P2X7 KO mice had a higher bacterial burden in the lungs than WT mice when infected with a lowvirulence strain, H37Rv Mtb [7].…”

“…The P2X7 receptor appears to be crucial during the immunological response against M. tuberculosis because P2X7 KO mice had a higher bacterial burden in the lungs than WT mice when infected with a lowvirulence strain, H37Rv Mtb [7]. On the other hand, the P2X7 receptor contributed to tissue damage in infection caused by a highly virulent strain of M. tuberculosis [27]. In addition, P2X7 KO mice infected with Toxoplasma gondii lost significantly more weight than WT C57BL/6 J mice after infection.…”

Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016

“…70 These mechanisms enable release of bacteria from the phagocytic cells and it has been observed that TB caused by hypervirulent mycobacteria is attenuated in mice that lack the P2X7 receptor and there is a decrease in disease dissemination. 71 The wild-type cells with active P2X7 die of necrosis which contributes to release of the hypervirulent mycobacteria. 71 Histological analyses also revealed less inflammation-induced damage in the knockout mice thus demonstrating that P2X7 signaling contributes to the pathology in a severe infection model.…”

“…71 The wild-type cells with active P2X7 die of necrosis which contributes to release of the hypervirulent mycobacteria. 71 Histological analyses also revealed less inflammation-induced damage in the knockout mice thus demonstrating that P2X7 signaling contributes to the pathology in a severe infection model. The group also noted that specific CD4 cells in the pulmonary parenchyma of mice infected with virulent mycobacterial strains are suppressed.…”