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 resistance.
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.
Tomioka
Haruaki
H
Department of Microbiology and Immunology, Shimane University School of Medicine, Shimane, Japan. tomioka@med.shimane-u.ac.jp
Sano
Chiaki
C
Sato
Katsumasa
K
Ogasawara
Keiko
K
Akaki
Tatsuya
T
Sano
Keisuke
K
Cai
Shan Shan
SS
Shimizu
Toshiaki
T
D000255:Adenosine Triphosphate / Q000008:administration & dosage*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001483:Base Sequence; D017291:Clarithromycin / Q000008:administration & dosage; D016207:Cytokines / Q000235:genetics; D003600:Cytosol / Q000201:enzymology; D004357:Drug Synergism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D015269:Mycobacterium avium Complex / Q000276:immunology; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012294:Rifamycins / Q000008:administration & dosage; D015398:Signal Transduction
D000900:Anti-Bacterial Agents; D016207:Cytokines; D012333:RNA, Messenger; D012294:Rifamycins; D000255:Adenosine Triphosphate; D010741:Phospholipases A; D054467:Phospholipases A2; D017291:Clarithromycin