Host-Directed Therapeutics: ATP as an Immunoadjunctive Agent for Chemotherapy against Mycobacterial Infections

Adenosine triphosphate (ATP) treatment of human macrophages, which possess both P2X7 and P2Y2 receptors, potentiates the activity of macrophages (MΦs) to kill mycobacterial organisms in a P2X7-dependent manner. ATP-mediated killing of mycobacterial organisms within MΦs is partly mediated by phospholipase D, which is linked to leukocyte antimicrobial mechanisms dependent on the mobilization of intracellular Ca and subsequent lysosomal fusion and acidification of mycobacteria-containing phagosomes. ATP-mediated killing of intramacrophage mycobacteria is also attributable to MΦ apoptosis induced by P2X7-mediated signaling. Furthermore, ATP signals transmitted through P2X7 receptors up-regulate MΦ antimycobacterial activity in a cytosolic phospholipase A2-dependent manner. Recently, it has been demonstrated that ATP directly inhibits the growth of various bacteria, including Staphylococcus, Pseudomonas, and mycobacteria. The antibacterial activity of ATP is attributable to its iron-chelating ability. This chapter describes the possible usefulness of ATP-based immunoadjunctive therapy in the clinical management of intractable mycobacteriosis, using antimicrobial chemotherapeutics.