The Balance of Apoptotic and Necrotic Cell Death in Mycobacterium tuberculosis Infected Macrophages Is Not Dependent on Bacterial Virulence

Abstract

BackgroundAn important mechanism of Mycobacterium tuberculosis pathogenesis is the ability to control cell death pathways in infected macrophages: apoptotic cell death is bactericidal, whereas necrotic cell death may facilitate bacterial dissemination and transmission.MethodsWe examine M.tuberculosis control of spontaneous and chemically induced macrophage cell death using automated confocal fluorescence microscopy, image analysis, flow cytometry, plate-reader based vitality assays, and M.tuberculosis strains including H37Rv, and isogenic virulent and avirulent strains of the Beijing lineage isolate GC1237.ResultsWe show that bacterial virulence influences the dynamics of caspase activation and the total level of cytotoxicity. We show that the powerful ability of M.tuberculosis to inhibit exogenously stimulated apoptosis is abrogated by loss of virulence. However, loss of virulence did not influence the balance of macrophage apoptosis and necrosis – both virulent and avirulent isogenic strains of GC1237 induced predominantly necrotic cell death compared to H37Rv which induced a higher relative level of apoptosis.ConclusionsThis reveals that macrophage necrosis and apoptosis are independently regulated during M. tuberculosis infection of macrophages. Virulence affects the level of host cell death and ability to inhibit apoptosis but other strain-specific characteristics influence the ultimate mode of host cell death and alter the balance of apoptosis and necrosis.

Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability

“…The balance of apoptosis/necrosis is an important mechanism to control intracellular mycobacterial growth and cell activation [46] Nonpathogenic strains such as BCG were reported to induce apoptosis whereas pathogens strain such as H37Rv promoted necrosis in cultured macrophages [44, 47, 48]. However, it has been reported that the balance of apoptosis and necrosis in M. tuberculosis infected macrophages depends on bacterial virulence and bacterial load [19]. …”

“…However, data have also reported that virulent and avirulent M. tuberculosis strains can both inhibit and promote apoptosis according to experimental conditions [16–19]. Despite accumulating data on macrophage activation and death by M. tuberculosis strains, BCG-mediated cellular activities in phagocytic cells remain relatively unexplored.…”

Mycobacterium tuberculosisPPE68 and Rv2626c genes contribute to the host cell necrosis and bacterial escape from macrophages

“…11,20 The association of intrinsic pathway of apoptosis and necrosis has been recently documented. 21,22 Our observation suggests that disturbance of the mitochondria membrane most likely is involved in the process of necrosis.…”

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…Epithelial cell induction of apoptosis is canonically regarded as a means through which the host can restrict pathogen replication in infected cells, without loss of membrane integrity and the secretion of DAMPs leading to hyper-inflammatory responses by the immune system (207). Many respiratory pathogens compromise pulmonary tolerance through the inhibition of apoptotic cell death and the upregulation of more inflammatory forms of cell death, such as necrosis, oncosis, or pyroptosis (208)(209)(210)(211). The hyper-inflammatory response to such forms of cell death is affected by immune cells sensing DAMPs.…”