Article
Differential regulation of E-NTPdases during Leishmania amazonensis lifecycle and effect of their overexpression on parasite infectivity and virulence
Registro en:
VIEIRA, Lisvane Paes et al. Differential regulation of E-NTPdases during Leishmania amazonensis lifecycle and effect of their overexpression on parasite infectivity and virulence. Parasitology International. v. 85, 102423, p. 1-10, July 2021.
1383-5769
10.1016/j.parint.2021.102423
Autor
Vieira, Lisvane Paes
Machado, Nathália Rocco
Mesquita, Anita Leocadio Freitas
Emiliano, Yago Sousa dos Santos
Vieira, André Luiz Gomes
Amaral, Elmo Eduardo de Almeida
Fernandes, José Roberto Meyer
Resumen
Infections caused by Leishmania amazonensis are characterized by a persistent parasitemia due to the ability of the
parasite to modulate the immune response of macrophages. It has been proposed that ecto-nucleoside triphosphate
diphosphohydrolase (E-NTPDases) could be able to suppress the host immune defense by reducing the ATP
and ADP levels. The AMP generated from E-NTPDase activity can be subsequently hydrolyzed by ectonucleotidases,
increasing the levels of adenosine, which can reduce the inflammatory response. In the present
work, we provide new information about the role of E-NTPDases on infectivity and virulence of L. amazonensis.
Our data demonstrate that not only the E-NTPDase activity is differentially regulated during the parasite
development but also the expression of the genes ntpd1 and ntpd2. E-NTPDase activity increases significantly in
axenic amastigotes and metacyclic promastigotes, both infective forms in mammalian host. A similar profile was
found for mRNA levels of the ntpd1 and ntpd2 genes. Using parasites overexpressing the genes ntpd1 and ntpd2,
we could demonstrate that L. amazonensis promastigotes overexpressing ntpd2 gene show a remarkable increase
in their ability to interact with macrophages compared to controls. In addition, both ntpd1 and ntpd2-overexpressing
parasites were more infective to macrophages than controls. The kinetics of lesion formation by
transfected parasites were similar to controls until the second week. However, twenty days post-infection, mice
infected with ntpd1 and ntpd2-overexpressing parasites presented significantly reduced lesions compared to
controls. Interestingly, parasite load reached similar levels among the different experimental groups. Thus, our
data show a non-linear relationship between higher E-NTPDase activity and lesion formation. Previous studies
have correlated increased ecto-NTPDase activity with virulence and infectivity of Leishmania parasites. Based in
our results, we are suggesting that the induced overexpression of E-NTPDases in L. amazonensis could increase
extracellular adenosine levels, interfering with the balance of the immune response to promote the pathogen
clearance and maintain the host protection. 2023
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