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Combined Effects of ATP on the Therapeutic Efficacy of Antimicrobial Drug Regimens against Mycobacterium avium Complex Infection in Mice and Roles of Cytosolic Phospholipase A₂-Dependent Mechanisms in the ATP-Mediated Potentiation of Antimycobacterial Host Resistance¹

Haruaki Tomioka^2,*, Chiaki Sano^*, Katsumasa Sato^*, Keiko Ogasawara^*,, Tatsuya Akaki^*,, Keisuke Sano^*,, Shan Shan Cai^* and Toshiaki Shimizu^*

^* Department of Microbiology and Immunology, Department of Otorhinolaryngology, and Department of Dermatology, Shimane University School of Medicine, Shimane, Japan

ATP, which serves as a mediator of intramacrophage signaling pathways through purinoceptors, is known to potentiate macrophage antimycobacterial activity. In this study we examined the effects of ATP in potentiating host resistance to Mycobacterium avium complex (MAC) infection in mice undergoing treatment with a drug regimen using clarithromycin and rifamycin and obtained the following findings. First, the administration of ATP in combination with the clarithromycin and rifamycin regimen accelerated bacterial elimination in MAC-infected mice without causing changes in the histopathological features or the mRNA expression of pro- or anti-inflammatory cytokines from those in the mice not given ATP. Second, ATP potentiated the anti-MAC bactericidal activity of macrophages cultivated in the presence of clarithromycin and rifamycin. This effect of ATP was closely related to intracellular Ca²⁺ mobilization and was specifically blocked by a cytosolic phospholipase A₂ (cPLA₂) inhibitor, arachidonyl trifluoromethylketone. Third, intramacrophage translocation of membranous arachidonic acid molecules to MAC-containing phagosomes was also specifically blocked by arachidonyl trifluoromethylketone. In the confocal microscopic observation of MAC-infected macrophages, ATP enhanced the intracellular translocation of cPLA₂ into MAC-containing phagosomes. These findings suggest that ATP increases the host anti-MAC resistance by potentiating the antimycobacterial activity of host macrophages and that the cPLA₂-dependent generation of arachidonic acid from the phagosomal membrane is essential for such a phenomenon.