Dying to live: how the death modality of the infected macrophage affects immunity to tuberculosis

Virulent Mycobacterium tuberculosis (Mtb) inhibits apoptosis and triggers necrosis of host macrophages to evade innate delay in the initiation of adaptive immunity. Necrosis is a mechanism used by bacteria to exit macrophage, evade the host defenses, and disseminate while apoptosis is associated with diminished pathogen viability. We have recently demonstrated that eicosanoids regulate cell death program of either human or murine macrophages infected with Mtb. We have defined prostaglandin E2 (PGE2) as a pro-apoptotic host lipid mediator which protects against necrosis. In contrast, lipoxin A4 (LXA4) is a pro-necrotic lipid mediator which suppresses PGE2 synthesis, resulting in mitochondrial damage and inhibition of plasma membrane repair mechanisms; this ultimately leads to the induction of necrosis. Thus, the balance between PGE2 and LXA4 determines whether Mtb-infected macrophages undergo apoptosis or necrosis and this balance determines the outcome of infection.