Manipulation of cell-death modality has been successfully used by other intracellular pathogens such as Chlamydia, Legionella pneumophila, Listeria monocytogenes, Shigella flexineri, and Salmonella enterica subsp. enterica serovar Typhimurium [28–30]. It has been demonstrated that host-cell apoptosis confers protection to the host, once the uptake of apoptotic bodies derived from macrophages by dendritic cells allows an effective activation of the immune response [31]. In contrast, host-cell necrosis can benefit the pathogen because disruption of the

cell membrane releases the bacteria to efficiently spread and infect adjacent cells [32]. Recently, descriptions of the manipulation of cell-death fate by Mtb have shown that

a virulent bacillus, the H37Rv strain, caused macrophage necrosis whereas the attenuated strain H37Ra was related to apoptotic death [12]. Likewise, a Ndk- (nucleoside diphosphate kinase) knockout selleck products Mtb showed reduced virulence, which was demonstrated by the susceptibility to macrophage microbicidal activity and increased ability to induce host-cell apoptosis [33]. this website Pulmonary macrophages are the primary niches for Mtb replication, thus host resistance is critically dependent on innate immune functions played by these cells. Palbociclib chemical structure In this scenario, proinflammatory cytokines and nitric oxide (NO) are essential for host control of Mtb. Macrophage recognition and phagocytosis of Mtb stimulates mostly the production of TNF-α, IL-1α and β, and IL-6, which are fundamental for the resolution

of Mtb infection in mice [18]. Our results highlighted the proinflammatory response triggered by 97-1505 Mtb very isolate, which induced a higher production of those cytokines by alveolar macrophages than the isolate 97-1200. Surprisingly, the higher production of proinflammatory cytokines did not result in better outcome for the host cell, as shown by the decreased macrophage survival. Stimulation of NO generation can cause oxidative stress leading to dysfunction in mitochondrial respiration and also block caspase-3 activity by nitrosylation, which may inhibit apoptosis and thereby promote necrosis [34]. Beyond the effects on the immune response, TNF-α has been associated with necrosis in a caspase-independent mechanism through activation of receptor TNFR1 and engagement of RIP1 kinase [34]. Recently, it was suggested that alveolar macrophages infected by an attenuated BCG (Bacillus Calmette–Guérin) show high expression of the TNF-α-receptor TNFR1 associated with increased cell apoptosis [35]. However, in that particular study, only apoptosis rate was analysed and necrosis was not shown. In addition, host-cell necrosis induced by the T3SS pore-forming protein, YopB, from pathogenic Yersinia has been associated with increased production of proinflammatory cytokines, such as IL-1β and TNF-α [36].