Purinergic Signalling (2007) 3:83–90 (Fig. 1) [23, 41]. A more recent study showed that, when combined, two loss-of-function polymorphisms in human P2X7 receptors impair ATPe-mediated apoptosis, despite the normal killing of BCG bacillus [28], reinforcing the view that the apoptosis of macrophages is not necessary for the elimination of mycobacteria. In fact, it was recently shown [42] that cyclosporine A, an inhibitor of the mitochondrial permeability transition, increases the survival of human monocyte-derived macro- phages infected with M. tuberculosis, restores P2X7 function and enhances antimycobacterial activity. Con- versely, M. tuberculosis has developed mechanisms to evade P2X7-triggered mechanisms, since it can secrete a nucleoside diphosphate kinase that produces ATP and kills macrophages through a P2X7-dependent mechanism [14]. New experiments are needed to clarify the role played by ATPe in killing intracellular pathogens and inducing host- cell death. Inhibition of chlamydial infection in macrophages The Chlamydia species are obligate intracellular bacteria that infect mainly epithelial mucosa, where they survive 85 within intracellular vacuoles that avoid fusion with host-cell lysosomes [6, 43]. Different strains of C. trachomatis are responsible for the infection of genital and ocular tissue in humans [44–48]. C. pneumoniae is a common cause of community-acquired pneumonia in humans and is associated with an increased risk for atherosclerosis [44, 49]. Both C. trachomatis and C. pneumoniae can invade epithelial cells and macrophages in vitro and in vivo [49, 50]. It was recently shown that ATPe inhibits the infection of macrophages by the murine species of C. trachomatis, C. muridarum, through a mechanism that required PLD activation and fusion between lysosomes and the Chlamyd- ia vacuoles [51]. The effect of ATPe was dependent on the presence of the P2X7 receptor, since there was no PLD activation nor killing of chlamydiae in infected macro- phages that had been isolated from P2X7-deficient mice. Although P2X7 ligation also led to macrophage death, the inhibition of PLD prevented chlamydial killing but had no effect on macrophage death, suggesting that PLD activation was directly responsible for the inhibition of chlamydial infection (Table 1). Moreover, fusion between lysosomes and chlamydial vacuoles preceded macrophage death, further strengthening the conclusion that the killing of chlamydiae is independent of host-cell death [51]. Fig. 1 ATP released from infected cells undergoing necrosis or sites of inflammation can bind to the P2X7 receptor on neighbouring macro- phages and other cells. Ligation of the P2X7 receptor initiates signalling through several pathways, which result in the activation of caspase-1, activation of phospholipase D (PLD) and, ultimately, cell death. Caspase-1 activation stimulates the inflammatory response by the cleavage of pro-IL-1β and secretion of the mature cytokine. PLD activation modifies membrane trafficking in the cell, which can induce fusion between lysosomes and vacuoles, harbouring intracellular pathogens such as mycobacteria and chlamydiae. The death of macrophages is partly necrotic, which may amplify inflammation even further, through the ligation of P2X7 receptors on other cells. Some extracellular ATP may also bind to other P2 receptors, which may inhibit infection by activating as-yet-uncharacterised pathways