Role of cAMP Homeostasis in Intra-Macrophage Survival and Infectivity of Unicellular Parasites likeLeishmania

Abstract

Unicellular eukaryotic pathogen Leishmania donovani, an intra-macrophage protozoan parasite, on exposure to phagolysosome conditions (PC) of mammalian macrophages, show increased cAMP level and cAMP-dependent protein kinase A (PKA) resulting in resistance to macrophage oxidative burst. In order to have a comprehensive understanding of cAMP signaling and their contribution to infectivity, studies were carried out on all the enzymes associated with cAMP metabolism such as adenylate cyclase, phosphodiesterase, pyrophosphatase and the regulatory and catalytic subunits of PKA. This chapter deals in detail the contribution of these components of cAMP signaling in cAMP homeostasis of the parasite as well as their role on successful host-parasite interaction leading to intracellular parasite survival and establishment of infection. Finally, a discussion is made about how these observations might be exploited for developing drug candidates targeting parasite specific features.

Repurposing approved protein kinase inhibitors as potent anti-leishmanials targeting Leishmania MAP kinases

“…A great diversity of different forms of human leishmaniasis are caused by 20 different species of Leishmania. Among the different types of leishmaniasis, visceral leishmaniasis is the most fatal form of the disease caused by Leishmania donovani that thrives as promastigote in sandfly gut at 22°C at a m pH 7.4 and at 37°C at a pH 5.5 in the mammalian macrophages where it transforms into amastigotes [1]. Differentiation of promastigotes to amastigotes is a controlled process where Leishmania proteins undergo post-translational modifications like methylation, acetylation, glycosylation, fucosylation, and phosphorylation [2].…”