E-NTPDases: Possible Roles on Host-Parasite Interactions and Therapeutic Opportunities

Abstract

Belonging to the GDA1/CD39 protein superfamily, nucleoside triphosphate diphosphohydrolases (NTPDases) catalyze the hydrolysis of ATP and ADP to the monophosphate form (AMP) and inorganic phosphate (Pi). Several NTPDase isoforms have been described in different cells, from pathogenic organisms to animals and plants. Biochemical characterization of nucleotidases/NTPDases has revealed the existence of isoforms with different specificities regarding divalent cations (such as calcium and magnesium) and substrates. In mammals, NTPDases have been implicated in the regulation of thrombosis and inflammation. In parasites, such as Trichomonas vaginalis, Trypanosoma spp., Leishmania spp., Schistosoma spp. and Toxoplasma gondii, NTPDases were found on the surface of the cell, and important processes like growth, infectivity, and virulence seem to depend on their activity. For instance, experimental evidence has indicated that parasite NTPDases can regulate the levels of ATP and Adenosine (Ado) of the host cell, leading to the modulation of the host immune response. In this work, we provide a comprehensive review showing the involvement of the nucleotidases/NTPDases in parasites infectivity and virulence, and how inhibition of NTPDases contributes to parasite clearance and the development of new antiparasitic drugs.

Overexpression of TcNTPDase-1 Gene Increases Infectivity in Mice Infected with Trypanosoma cruzi

“…During infectious processes, the presence of serum ATP as a result of tissue injury or lysis of infected cells, signals the formation and intensity of the immune response [ 48 ]. T. cruzi has a TcNTPDase on its surface that is capable of hydrolyzing ATP into ADP and the latter into AMP, preventing or hindering the formation of an effective immune response [ 33 ]. A recent study, by our group, demonstrated that the culture of VERO cells infected with a hemi-knockout clone of T. cruzi for the TcNTPDase-1 gene (KO +/−) was able to decrease not only adhesion, but also the infection of these cells in this in vitro model [ 38 ].…”

“…NTPDases have been described as being associated with several cellular functions, such as differentiation, multiplication, division, and apoptosis [ 33 ]. Present in various cell types and tissues, analogs of these enzymes are also found in the membranes of protozoan microorganisms.…”

“…Using CD39 antibody Western blot analysis showed that NTPDase-1 was poorly expressed in the blood promastigote form and significantly increased in axenic amastigotes and reached the highest expression level in metacyclic promastigotes [ 26 ]. Trypanosomatids are not able to produce their own purines to carry out their metabolic activities [ 32 , 33 ]. Some studies suggest that the uptake of these exogenous purines is performed by plasma enzymes, such as NTPDases [ 32 ].…”

“…In the first case, the enzymes act by deactivating the defense responses, decreasing the levels of ATP and ADP, by extracellular forms (trypomastigote), since the immune system of the hosts is regulated by the levels of ATP and ADP, as well as by the ADP-dependent platelet aggregation [ 34 , 35 ]. In the second case, as trypanosomatids do not synthesize purines, the amastigote, which are replicating forms, use these enzymes to obtain the machinery necessary for their own metabolism [ 33 ].…”

“…The literature has shown that these enzymes are related to the trypanosomatid infectivity and virulence processes [ 37 , 39 ]. However, at present, most studies focused on the enzymatic activity of ecto-NTPDases in intact parasites or plasma membrane fractions [ 33 , 40 ]. Therefore, there is a lack of information on the specific contribution of each of these enzymes during these cellular processes and the use of mice models in CD has proved to be important to gain insight into aspects of disease progression in humans [ 41 , 42 , 43 , 44 ].…”