Mycobacterium tuberculosis Induces an Atypical Cell Death Mode to Escape from Infected Macrophages

BACKGROUND: Macrophage cell death following infection with Mycobacterium tuberculosis plays a central role in tuberculosis disease pathogenesis. Certain attenuated strains induce extrinsic apoptosis of infected macrophages but virulent strains of M. tuberculosis suppress this host response. We previously reported that virulent M. tuberculosis induces cell death when bacillary load exceeds approximately 20 per macrophage but the precise nature of this demise has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the characteristics of cell death in primary murine macrophages challenged with virulent or attenuated M. tuberculosis complex strains. We report that high intracellular bacillary burden causes rapid and primarily necrotic death via lysosomal permeabilization, releasing hydrolases that promote Bax/Bak-independent mitochondrial damage and necrosis. Cell death was independent of cathepsins B or L and notable for ultrastructural evidence of damage to lipid bilayers throughout host cells with depletion of several host phospholipid species. These events require viable bacteria that can respond to intracellular cues via the PhoPR sensor kinase system but are independent of the ESX1 system. CONCLUSIONS/SIGNIFICANCE: Cell death caused by virulent M. tuberculosis is distinct from classical apoptosis, pyroptosis or pyronecrosis. Mycobacterial genes essential for cytotoxicity are regulated by the PhoPR two-component system. This atypical death mode provides a mechanism for viable bacilli to exit host macrophages for spreading infection and the eventual transition to extracellular persistence that characterizes advanced pulmonary tuberculosis

Value of lung biopsy in pulmonary diseases in children

Purpose: Open lung biopsy (OLB) is claimed to be a sensitive tool for the diagnosis of interstitial lung disease. It is reported to be associated with significant morbidity and mortality. Aim: Evaluate whether lung biopsy helped us to make a specific diagnosis, it had resulted in change in therapy and assessment of its morbidity and mortality. Materials and Methods: This was a retrospective analysis of 91 lung biopsies performed in 83 patients between January 2000 and December 2003. These children were allocated to three groups: a. Primary pulmonary pathology (22), b. Immunocompromised (49) i. Primary immunodeficiency (10), ii. Postchemotherapy and BMT (39), c. Pulmonary metastases from solid tumors (20) Results: A specific diagnosis was reached in 87/91 children (95%), but this resulted in a change in therapy (excluding lung meet) in only 23/71 (32%). It is lower in those postchemo/BMT 8/39 (20.6%). Postoperative morbidity occurred in 11/91 (12%) but procedure-related morbidity was only (3.2%). Death within a month of the biopsy occurred in six children (6.5%), with one (1.1%) procedure-related. Conclusion: 1. OLB is a safe procedure at our institution. 2. OLB is a sensitive tool to determine the specific cause of pulmonary infiltrate. 3. Change in therapy expected to be only in 32% of patients and even lower in postchemotherapy and BMT children

Value of lung biopsy in pulmonary diseases in children

Purpose: Open lung biopsy (OLB) is claimed to be a sensitive tool for the diagnosis of interstitial lung disease. It is reported to be associated with significant morbidity and mortality. Aim: Evaluate whether lung biopsy helped us to make a specific diagnosis, it had resulted in change in therapy and assessment of its morbidity and mortality. Materials and Methods: This was a retrospective analysis of 91 lung biopsies performed in 83 patients between January 2000 and December 2003. These children were allocated to three groups: a. Primary pulmonary pathology (22), b. Immunocompromised (49) i. Primary immunodeficiency (10), ii. Postchemotherapy and BMT (39), c. Pulmonary metastases from solid tumors (20) Results: A specific diagnosis was reached in 87/91 children (95%), but this resulted in a change in therapy (excluding lung meet) in only 23/71 (32%). It is lower in those postchemo/BMT 8/39 (20.6%). Postoperative morbidity occurred in 11/91 (12%) but procedure-related morbidity was only (3.2%). Death within a month of the biopsy occurred in six children (6.5%), with one (1.1%) procedure-related. Conclusion: 1. OLB is a safe procedure at our institution. 2. OLB is a sensitive tool to determine the specific cause of pulmonary infiltrate. 3. Change in therapy expected to be only in 32% of patients and even lower in postchemotherapy and BMT children