Apoptosis is an innate defense function of macrophages against Mycobacterium tuberculosis

Abstract

Two different forms of death are commonly observed when Mycobacterium tuberculosis (Mtb)-infected macrophages die: (i) necrosis, a death modality defined by cell lysis and (ii) apoptosis, a form of death that maintains an intact plasma membrane. Necrosis is a mechanism used by bacteria to exit the macrophage, evade host defenses, and spread. In contrast, apoptosis of infected macrophages is associated with diminished pathogen viability. Apoptosis occurs when tumor necrosis factor activates the extrinsic death domain pathway, leading to caspase-8 activation. In addition, mitochondrial outer membrane permeabilization leading to activation of the intrinsic apoptotic pathway is required. Both pathways lead to caspase-3 activation, which results in apoptosis. We have recently demonstrated that during mycobacterial infection, cell death is regulated by the eicosanoids, prostaglandin E2 (proapoptotic) and lipoxin (LX)A4 (pronecrotic). Although PGE2 protects against necrosis, virulent Mtb induces LXA4 and inhibits PGE2 production. Under such conditions, mitochondrial inner membrane damage leads to macrophage necrosis. Thus, virulent Mtb subverts eicosanoid regulation of cell death to foil innate defense mechanisms of the macrophage.

Immunity and Immunopathology in the Tuberculous Granuloma

“…Based on in vitro studies, it has been proposed that apoptosis is a host strategy that is detrimental to the infecting mycobacteria, in contrast to necrosis, which favors bacterial growth (Fratazzi et al 1997;Oddo et al 1998;Keane et al 2002;Gan et al 2008;Behar et al 2011). Some of these studies have caveats: the use of genetically undefined mutant strains and/ or additional agents to induce specific apoptotic death pathways that might override mycobacterially induced pathways (Molloy et al 1994;Fratazzi et al 1997;Oddo et al 1998;Keane et al 2000;Gan et al 2008).…”

Interaction of Mycobacterium tuberculosis with Host Cell Death Pathways

“…A correlation between virulence of Mtb and its capacity to induce mitochondrial-dependent necrosis was first proposed by studies comparing the capacities of Mtb H37Rv and the attenuated Mtb H37Ra strains to disrupt mitochondrial function (Chen et al 2006;Behar et al 2011). Indeed only Mtb H37Rv led to an early mitochondrial transmembrane potential loss caused by mitochondrial permeability transition (MPT) pore complex.…”

“…The literature on the inhibition of host cell apoptosis by Mtb has been reviewed recently (Abebe et al 2011;Behar et al 2011;Briken 2013). The mechanisms of inhibition include the up-regulation of host cell antiapoptosis signaling proteins such as the Bcl-2 family member Mcl-1 (Sly et al 2003) or the Bfl-1 protein (Kausalya et al 2001).…”

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity

“…Necrosis is characterized by metabolic collapse and loss of membrane integrity and is used by M. tuberculosis to exit destroyed cells, evade host defenses, and disseminate to other tissues and eventually to new hosts (10). By contrast, apoptosis of the infected macrophages helps the host to control the bacterial infection (11). Virulent M. tuberculosis strains induce a necrosislike cell death and concomitantly suppress apoptosis of macrophages (12).…”