PLoS Pathogens · 2014 · 101 citations · 50 references
Veterinary MedicineInfectious DiseasesMicrobiologyHost-pathogen InteractionsInflammationInnate ImmunityBacterial InfectionsMacrophage BiologyPulmonary InfectionsPulmonary InflammationPulmonary TuberculosisRespiratory InfectionsGranulomatous LesionsInflammatory Cytokine ProductionMycobacterial DiseaseMycobacterium Tuberculosis InfectionMycobacterium Tuberculosis PathogenesisP2x7 Receptor SignalingPulmonary PathogenesisTuberculosis Pathology
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.
50
Cryopyrin activates the inflammasome in response to toxins and ATP
Sanjeev Mariathasan, David S. Weiss, Kim Newton et al. · Nature · 2006 · 3K citations
Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation
Braedon McDonald, Keir Pittman, Gustavo Batista Menezes et al. · Science · 2010 · 1.2K citations