Modulation and increase of cellular signaling of the host macrophage as a means of intracellular Leishmania elimination

Beside their direct specific drug susceptibility on the protozoa, additional anti-leishmanial activity of antimony compounds is also related to the intracellular

pump

-ADP

Active efflux ^

Figure 23.6 Possible mechanisms of action and resistance of SbV in Leishmania pump

ATP "

-ADP

Active efflux ^

Figure 23.6 Possible mechanisms of action and resistance of SbV in Leishmania clearance of the parasite which is medicated by interferon gamma (INF-7) activity via the regulation of the chemotherapy response of host cytokines. INF-7 plays an important role in eliminating intracellular Leishmania and the impaired INF-7 signaling was detected in Leishmania-infected macrophage suggested that anti-leishmanial activity of SbV may derive from an increase of cell signaling.120,121

Massive generation of superoxide anion (O2') and other reactive oxygen species (ROS) such as hydroxyl radicals (OH'), hydrogen peroxide (H2O2) and singlet oxygen (1O2) stimulated by particles or soluble mediators are known as respiratory burst. Respiratory burst activity plays an important role in the destruction of infected pathogens by phagocytes.122 Activated macrophages kill intracellular parasites by generation of ROS and nitric oxide in Leishmania infection,123 126 and the down-regulation of this immune defense response by Leishmania species is related to the resistance of the parasites to oxygen-dependent toxicity.127,128 Treatment of SbV (Pentostam®) promotes the generation of ROS in vivo, an observation known as 'priming', when phagocytes' respiratory burst is enhanced by the treatment of low concentration of drugs.129 An accelerated and enhanced overall efficiency is observed when INF-7 is synergistically injected with antimony.130 Thus the effect of antimony on host cell reactivity may contribute to the mechanisms of action of antimony drugs.

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