Tinkering with targeting nucleotide signaling for control of intracellular Leishmania parasites.

Nucleotides are one of the most primitive extracellular signalling molecules across all phyla and regulate a multitude of responses. The biological effects of extracellular nucleotides/sides are mediated via the specific purinergic receptors present on the cell surface. In mammalian system, adenine nucleotides are the predominant nucleotides found in the extracellular milieu and mediate a constellation of physiological functions. In the context of host-pathogen interaction, extracellular ATP is recognized as a danger signal and potentiates the release of pro-inflammatory mediators from activated immune cells, on the other hand, its breakdown product adenosine exerts potential anti-inflammatory and immunosuppressive actions. Therefore, it is increasingly apparent that the interplay between extracellular ATP/adenosine ratios has a significant role in coordinating the regulation of the immune system in health and diseases. Several pathogens express ectonucleotidases on their surface and exploit the purinergic signalling as one of the mechanisms to modulate the host immune response. Leishmania pathogens are one of the most successful intracellular pathogens which survive within host macrophages and manipulate protective Th1 response into disease promoting Th2 response. In this review, we discuss the regulation of extracellular ATP and adenosine levels, the role of ATP/adenosine counter signalling in regulating the inflammation and immune responses during infection and how Leishmania parasites exploit the purinergic signalling to manipulate host response. We also discuss the challenges and opportunities in targeting purinergic signalling and the future prospects.