Extracellular nucleotide metabolism in Leishmania: influence of adenosine in the establishment of infection

Abstract

Leishmaniasis is a parasitic disease with a variety of clinical forms, which are related to the Leishmania species involved. In the murine model, Leishmania amazonensis causes chronic non-healing lesions in Leishmania braziliensis- or Leishmania major-resistant mouse strains. In this study, we investigated the involvement of the pathway of extracellular nucleotide hydrolysis, with special focus on the role of extracellular adenosine, in the establishment of Leishmania infection. Our results show that the more virulent parasite--L. amazonensis--hydrolyzes higher amounts of ATP, ADP and AMP than the two other species, probably due to the higher expression of membrane NTPDase. Corroborating the idea that increased production of adenosine is important to lesion development and establishment of tissue parasitism, we observed that increased 5'-nucleotidase activity in L. braziliensis or addition of adenosine at the moment of infection with this parasite resulted in an increase in lesion size and parasitism as well as a delay in lesion healing. Furthermore, inhibition of adenosine receptor A2B led to decreased lesion size and parasitism. Thus, our results suggest that the conversion of ATP, a molecule with pro-inflammatory activity, into adenosine, which possesses immunomodulatory properties, may contribute to the establishment of infection by Leishmania.

Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A2B adenosine receptor activation

“…• C. Metacyclic promastigotes were purified by gradient centrifugation of parasites at the stationary phase of culture (day 5) over Ficoll 400 (SigmaAldrich), as previously described [3].…”

“…Leishmania infections can result in a wide spectrum of clinical manifestations and disease outcome is determined both by the parasite species and by Correspondence: Dr. Luís C. C. Afonso e-mail: afonso@nupeb.ufop.br the host immune response. Leishmania amazonensis differs from other species because it is able to cause chronic non-healing lesions in mouse strains genuinely resistant to other Leishmania species, such as Leishmania braziliensis and Leishmania major [1][2][3]. In humans, L. amazonensis causes diffuse cutaneous leishmaniasis, a condition characterised by a lack of antigen-specific T-cell responses against the parasite [4].…”

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

“…Then, in 2008 Marques-da-Silva studied the influence of extracellular nucleotides and adenosine on Leishmania infection in a murine model susceptible to infection by L. amazonensis but resistant to infections by L. braziliensis and L. major. This work described that the more virulent parasite (L. amazonensis) hydrolyzed higher amounts of ATP, ADP and AMP and that this result correlated with higher expression of E-NTPDase-2 on the L. amazonensis membrane [44] . Furthermore they have shown that the presence of adenosine or higher ecto-AMPase activity by 5'-NT on the parasite led to an increase in lesion size, parasitism and a delay in lesion healing.…”

“…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] .…”

“…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] . In Leishmania, literature data suggest that E-NTPDases also participate in the establishment of infection [41,44] and in the development of clinical signs [42] . In these organisms, the following two E-NTPDases were identified: E-NTPDase-1 and E-NTPDase-2.…”