Leishmania infantum Ecto-Nucleoside Triphosphate Diphosphohydrolase-2 is an Apyrase Involved in Macrophage Infection and Expressed in Infected Dogs

Vasconcellos, Raphael de Souza; Mariotini-Moura, Christiane; Gomes, Rodrigo Saar; Serafim, Tiago D.; Firmino, Rafaela de Cássia; Bastos, Matheus Silva e; Castro, Francine Attié de; Oliveira, Claudia Miranda de; Borges-Pereira, Lucas; Souza, Anna Cláudia Alves de; Souza, Ronny Francisco de; Gomez, Gabriel; Pinheiro, Aimara da Costa; Maciel, Talles Eduardo Ferreira; Silva-Júnior, Abelardo; Bressan, Gustavo Costa; Almeida, Márcia Rogéria de; Baqui, Munira Muhammad Abdel; Afonso, Luís Carlos Crocco; Fietto, Juliana Lopes Rangel

doi:10.1371/journal.pntd.0003309

Cited by 23 publications

(26 citation statements)

References 46 publications

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“…However, the proliferation of the parasite inside macrophages was not affected. These results suggested the existence of a possible binding site (like an unknown receptor) for the Lic-E-NTPDase2 in macrophages that could participate in facilitating adhesion and infection [46] . These data are in accordance with previous results also observed in T. cruzi [45] .…”

Section: Biochemical and Biological Roles Of Ecto-nucleotidases And Tmentioning

confidence: 88%

“…The GP63, a zinc-metalloprotease named glycoprotein 63 (GP63), is another critical virulence factor that has been fully explored [34][35][36][37][38] . However, the E-NTPDases (ecto-nucleoside triphosphate diphosphohydrolases), while less-extensively studied, have been demonstrated and believed to be important infectivity and virulence factors [39][40][41][42][43][44][45][46][47][48] .…”

Section: Leishmania Braziliensis Is Responsible For Most Cases Of MLmentioning

confidence: 99%

“…A summary of the general view of ecto-nucleotidases, ecto-nucleosides and mammalian immune system homeostasis control is shown in Figure 1. Additionally, E-NTPDases had been found in several protozoan parasites including the following: Toxoplasma gondii [72] Trichomonas vaginalis [73] Trypanosoma cruzi [40] , Leishmania amazonensis [74] , Leishmania braziliensis [75] and other organisms [46] . In Trypanosomatids, these enzymes are important components of the pathway of the salvation of purines [40] because these parasites are unable to perform de novo synthesis of purines [76] .…”

Section: Biochemical and Biological Roles Of Ecto-nucleotidases And Tmentioning

confidence: 99%

“…Unfortunately, the literature on this topic is not uniform and other research groups have named these proteins differently, e.g., E-NTPDase-2 (approximately 40 kDa) is also called as ATPdiphosphohydrolase or nucleoside diphosphatase [48] . In order to stimulate a uniformity in the parasite E-NTPDase nomenclature, we have performed phylogenetic and bioinformatic analyses and proposed the following uniform nomenclature: TpNTPDase-1 and TpNTPDase-2 (Tp = trypanosomatids NTPDases; isoform 1 is approximately 70 kDa and isoform 2 is 40 kDa) [46] .…”

Section: Biochemical and Biological Roles Of Ecto-nucleotidases And Tmentioning

confidence: 99%

“…There is a direct relationship between the ability to hydrolyze nucleotides and the ability to sustain infection [39, 42-44, 47, 74, 78, 115-119] . It has also been shown recently that the E-NTPDase of parasites can act as an adhesion protein during the early stages of infection [45,46,120] . Inhibiting Leishmania molecules that actively modulate the macrophage signaling pathways is essential to prevent the intracellular survival of Leishmania.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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The Leishmania-Macrophage Interactions: Role of E-NTPDases and Purinergic Signaling

et al. 2016

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Leishmaniasis comprises a group of diseases caused by protozoan parasites of the genus Leishmania. The transmission occurs by the bite of phlebotomine female sand flies of the genera Phlebotomus and Lutzomyia. In the mammalian host, these parasites infect and proliferate mainly into the macrophages, avoiding the harmful effects of the innate inflammatory response. It has been reported in several works that purinergic signaling, including purine receptors P1 and P2, are dynamically modulated during both the development and activation of cells from the immune system to achieve homeostasis or combat infections as well as harmful damage. Many pathogens are able to subvert the host immune response in order to promote the success or maintenance of infection. This subversion can be related to the influence of pathogens on purinergic signaling leading to decreased levels of the pro-inflammatory molecule ATP and increased levels of the immunosuppressive molecule adenosine. This scenario can be produced as the final product of the joint activity of E-NTPDases and 5'-ectonucleotidases. Thus, this review will discuss the cellular and molecular events occurring during the interaction of Leishmania and macrophages focusing on the purinergic signaling pathways and their relationships with ENTPDases from pathogenic species of Leishmania.

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Section: Biochemical and Biological Roles Of Ecto-nucleotidases And Tmentioning

confidence: 88%

Section: Leishmania Braziliensis Is Responsible For Most Cases Of MLmentioning

confidence: 99%

Section: Biochemical and Biological Roles Of Ecto-nucleotidases And Tmentioning

confidence: 99%

Section: Biochemical and Biological Roles Of Ecto-nucleotidases And Tmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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The Leishmania-Macrophage Interactions: Role of E-NTPDases and Purinergic Signaling

et al. 2016

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NTPDase activities: possible roles on Leishmania spp infectivity and virulence

Paes-Vieira

Gomes-Vieira

Meyer‐Fernandes

2018

Cell Biology International

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Nucleoside triphosphate diphosphohydrolases (NTPDases) are enzymes that belong to the GDA1/CD39 protein superfamily. These enzymes catalyze the hydrolysis of ATP and ADP to the monophosphate form (AMP). Biochemical characterization of the nucleotidases/NTPDases from various types of cells, including those from plants, animals, and pathogenic organisms, has revealed the existence of several isoforms with different specificities with respect to divalent cations (magnesium, calcium, manganese, and zinc) and substrates. In mammals, the NTPDases play important roles in the regulation of thrombosis and inflammation. In parasites of the genus Leishmania, the causative agents of leishmaniasis, two NTPDase isoforms, termed NTPDase-1 and NTPDase-2 have been described. Independently of their cellular localization, whether cell-surface localized, secreted or targeted to other organelles, in some Leishmania species these NTPDases could be involved in parasite growth, infectivity, and virulence. Experimental evidence has suggested that the hydrolysis of ATP and ADP by parasite ecto-nucleotidases can down-modulate the host immune response. In this context, the present work provides an overview of recent works that show strong evidence not only of the involvement of the nucleotidases/NTPDases in Leishmania spp infectivity and virulence but also of the molecular mechanisms that lead to the success of the parasitic infection.

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Magnesium-Dependent Ecto-ATP Diphosphohydrolase Activity in Leishmania donovani

et al. 2016

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In this work, we have described the expression of ecto-ATPDase on the external surface of Leishmania donovani. This enzyme has the ability to hydrolyze extracellular ATP. There is a low level of ATP hydrolysis in the absence of divalent cation 2.5 ± 0.51 nM Pi 10 cells/h which shows the divalent cation-dependent activity of this enzyme in the intact parasite. However, MgCl stimulated the ATP hydrolysis to a greater extent compared with CaCl and ZnCl. This activity was also observed when replaced by MnCl. The Mg-dependent ecto-ATPase activity was 46.58 ± 6.248 nM Pi 10 cells/h. The apparent K for ATP was 5.76 mM. Since Leishmania also possesses acid phosphatase activity and to discard the possibility that the observed ATP hydrolysis was due to acid phosphatase, the effect of pH was examined. In the pH range 6.0-9.0, in which the cells were viable, the phosphatase activity decreased while ATPase activity increased. To show that the observed ATP hydrolysis was not due to phosphatase or nucleotidase activity, certain inhibitors for these enzymes were tested. Vandate and NaF inhibited the phosphatase activity; Ammonium molybdate inhibited 5'-nucleotidase activity, but these inhibitors did not inhibit the observed ATP hydrolysis. However, when ADP was used as a substrate, there was no inhibition of ATP hydrolysis showing the possibility of ATP diphosphohydrolase activity. To confirm that this Mg-dependent ATPase activity is an ecto-ATPase activity, we used an impermeable inhibitor, 4,4'-diisothiocyanostilbene 2,-2'-disulfonic acid, as well as suramin, an antagonist of P2-purinoceptors and inhibitor of some ecto-ATPases. These two reagents inhibited the Mg-dependent ATPase activity in a dose-dependent manner. The presence of L. donovani E-NTPDase activity was demonstrated using antibodies against NTPDase by Western blotting and flow cytometry. The presence of Mg-dependent ATP diphosphohydrolase activity on the surface of L. donovani modulates the nucleotide concentration and protects the parasite from the lytic effects of the nucleotides mainly ATP. Ecto-ATPDase from L. donovani may be further characterized as a good antigen and as a target for immunodiagnosis and drug development, respectively.

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Leishmania infantum Ecto-Nucleoside Triphosphate Diphosphohydrolase-2 is an Apyrase Involved in Macrophage Infection and Expressed in Infected Dogs

Cited by 23 publications

References 46 publications

The Leishmania-Macrophage Interactions: Role of E-NTPDases and Purinergic Signaling

The Leishmania-Macrophage Interactions: Role of E-NTPDases and Purinergic Signaling

NTPDase activities: possible roles on Leishmania spp infectivity and virulence

Magnesium-Dependent Ecto-ATP Diphosphohydrolase Activity in Leishmania donovani

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