Adenosine and Immune Imbalance in Visceral Leishmaniasis: The Possible Role of Ectonucleotidases

Abstract

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is responsible for most Leishmania-associated deaths. VL represents a serious public health problem that affects many countries. The immune response in leishmaniasis is very complex and is poorly understood. The Th1 versus Th2 paradigm does not appear to be so clear in visceral leishmaniasis, suggesting that other immunosuppressive or immune-evasion mechanisms contribute to the pathogenesis of VL. It has been demonstrated that generation of adenosine, a potent endogenous immunosuppressant, by extracellular enzymes capable to hydrolyze adenosine tri-nucleotide (ATP) at the site of infection, can lead to immune impairment and contribute to leishmaniasis progression. In this regard, this paper discusses the unique features in VL immunopathogenesis, including a possible role for ectonucleotidases in leishmaniasis.

CD39 and CD73 in immunity and inflammation

“…Pathogens can also exploit ectonucleotidases located on the outer surface of a cell or tissue to generate an adenosine-rich milieu, which allows them to escape immune surveillance [81–85]. By contrast, in certain scenarios, CD39 and CD73 can also curb infections and associated inflammation and mortality [65,86].…”

“…By contrast, in certain scenarios, CD39 and CD73 can also curb infections and associated inflammation and mortality [65,86]. Increased expression and activity of the CD39/CD73 axis have been described during infections induced by several microorganisms, including protozoa (belonging to the genus Leishmania , Trypanosoma, Toxoplasma, Trichomonas , Giardia ) [81,83,87–91], fungi ( Candida parapsilosis ) [84], and bacteria [62,65,82,85,86, 92–94]. …”

Ecto-nucleotidases and Ecto-phosphatases from Leishmania and Trypanosoma Parasites

“…E-NPPs and alkaline phosphatases are capable of hydrolyzing not only nucleotides but also other substrates, and their roles in the control of purinergic signaling are still scarce (Zimmermann et al 2012 ). In the case of trypanosomatids, another remarkable nucleotidase is the ecto-3′nucleotidase/nuclease (ecto-3′NT/NU), an important source of adenosine via 3′AMP hydrolysis (Paletta-Silva and Meyer-Fernandes 2012 ). This section will discuss the metabolism of extracellular nucleotides, emphasizing the following topics: the purine salvage pathway; purinergic signaling in host immune response; and occurrence of E-NTPDases, ecto-5′NTs and ecto-3′NT/NUs in Leishmania and Trypanosoma species.…”

“…With respect to DC differentiation, chronic exposure to low concentrations of ATP drives DC maturation toward a phenotype favoring the development of Th2 response (Di Virgilio 2007 ). Massive discharge of ATP into the extracellular space can occur in acute situations, and the resulting activation of P2 receptors leads to proinfl ammatory effects by initiating a response characterized by the secretion of IFN-γ, IL-12, TNF-α and IL-1 (Di Virgilio 2007 ;Paletta-Silva and Meyer-Fernandes 2012 ).…”

“…Moreover, activation of A2 receptors is also involved in the inhibition of monocyte maturation and suppression of macrophage phagocytic function. It is noteworthy that adenosine can also inhibit adenylate cyclase if bound to A1 or A3 receptors; however, in purinergic signaling the fi nal response depends on several factors, including receptor expression and sensitivity (Paletta-Silva and Meyer-Fernandes 2012 ).…”