Differential regulation of E-NTPdases during Leishmania amazonensis lifecycle and effect of their overexpression on parasite infectivity and virulence.

Autor: Paes-Vieira L; Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Electronic address: lisvane@bioqmed.ufrj.br., Rocco-Machado N; Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Freitas-Mesquita AL; Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Dos Santos Emiliano YS; Laboratório de Bioquímica de Tripanosomatideos, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz-FIOCRUZ, Pavilhão Leônidas Deane, 4° andar, sala 405A, Manguinhos, 21045-900 Rio de Janeiro, RJ, Brazil., Gomes-Vieira AL; Instituto de Química, Departamento de Bioquímica, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil., de Almeida-Amaral EE; Laboratório de Bioquímica de Tripanosomatideos, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz-FIOCRUZ, Pavilhão Leônidas Deane, 4° andar, sala 405A, Manguinhos, 21045-900 Rio de Janeiro, RJ, Brazil., Meyer-Fernandes JR; Laboratório de Bioquímica Celular, Instituto de Bioquímica Médica Leopoldo de Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil. Electronic address: meyer@bioqmed.ufrj.br.
Jazyk: angličtina
Zdroj: Parasitology international [Parasitol Int] 2021 Dec; Vol. 85, pp. 102423. Date of Electronic Publication: 2021 Jul 21.
DOI: 10.1016/j.parint.2021.102423
Abstrakt: 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 ecto-nucleotidases, 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.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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