Ecto-ATPase activity on the surface of Trypanosoma cruzi and its possible role in the parasite?host cell interaction

Abstract

This study describes the possible role of Mg(2+)-dependent ecto-ATPase activity on the Trypanosoma cruzi-host cell interaction. Mg(2+)-dependent ecto-ATPase activity is observed on the cell body and flagellar membranes of the parasite and is about 20 times greater in trypomastigotes, as compared with epimastigotes. Suramin (a competitive antagonist of P2 receptors) and the impermeant agent 4,4'-diisothiocyanostylbene 2',2'-disulfonic acid (DIDS), both inhibitors of ecto-ATPases, strongly inhibited ATPase activity and the adhesion and internalization of both evolutive forms by mouse resident macrophages. Suramin inhibited the growth of epimastigotes, suggesting a direct participation of ecto-ATPase activity in this process. To overcome the presence of suramin in the culture medium during the time of growth, Mg(2+) ecto-ATPase activity was enhanced 4-fold, as compared with control parasites. The over-expression in enzyme activity was followed by a dramatic increase in the adhesion of epimastigotes to resident macrophages above the level observed for non-treated parasites.

Contributions of Ultrastructural Studies to the Cell Biology of Trypanosmatids: Targets for Anti-Parasitic Drugs

“…Treatment of T. cruzi with suramin, a symmetrical polysulfonated derivative of urea used in the prophylactic treatment of human trypanosomiasis in Africa, caused increased activity of a Mg 2+ ecto-ATPase and the FRA antigen and redistribution of negative surface charges. Alterations in extracellular components in the region of adhesion between the cell body and the flagellum and an increase in the adhesion of epimastigotes to resident macrophages were also observed [92,98,99] (Fig. 2L). …”

Implication of purinergic signaling pathways in clinical management of Chagas' disease

“…All those mediators are highly toxic to T. cruzi 18 . It has been described that Tc-ENTPDase-1 might play a modulatory role in response to these toxic mediators and in consequence affect purine recovery pathways, which are necessary for nutrition and to maintain parasite viability; beyond this, they can be involved in inflammatory processes, modulation of the host immune system and consequently increase the virulence mechanisms of T. cruzi 17,19,20 . A virulence key mechanism related to Tc-ENTPDase-1 presents a relation with enzyme capacity that interferes with extracellular ATP signals and interrupts purinergic signalling, limiting mechanisms of host defences.…”

“…A virulence key mechanism related to Tc-ENTPDase-1 presents a relation with enzyme capacity that interferes with extracellular ATP signals and interrupts purinergic signalling, limiting mechanisms of host defences. This activity seems to be dependent on the presence of divalent cations such as calcium and magnesium 17,19 . The main consequence of extracellular ATP hydrolysis by T. cruzi catalysed by Tc-ENTPDase-1 is purine recovery from their hosts 16 .…”

“…Purines represent precursor molecules fundamental for DNA and RNA synthesis, which are carriers of high-energy phosphate bonds, constituents of coenzymes and modulators of certain enzymatic reactions 21 . This makes the parasite to develop an absolute need for purines once T. cruzi does not have the machinery to synthesise its own purine ring de novo 19 . The inability of T. cruzi to produce nucleobases (adenine, guanine, xanthine, hypoxanthine) and nucleosides (adenosine, guanosine and inosine) makes this parasite to transport these compounds across its plasma membrane.…”

“…Although these authors pointed the involvement of suramin on biological mechanisms related to Tc-NTPDase inhibition, due to binding to P2 receptors, this activity has been demonstrated only in vitro. Relative ineffectiveness of suramin has been demonstrated in studies in vivo and there are urgent necessities of controlled preclinical and clinical studies to define the molecular mechanisms involved in the modulation of parasite biology 19,20 . Thus, we considered suramin and purinergic signalling inhibition as a promising target in the clinical management of Chagas disease.…”