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Intravascular schistosomes may control immune and hemostatic responses by regulating the nature and amount of selected host purinergic signaling molecules - such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and nicotinamide adenine dinucleotide (NAD) - surrounding them. Such metabolites are collectively known as the worm's 'purinergic halo'. Host-interactive, membrane-bound, tegumental ectonucleotidases, notably SmATPDase1, SmNPP5, SmAP and SmNACE, can degrade proinflammatory, prothrombotic and immunomodulatory purinergic metabolites like those listed. A common catabolic product is the anti-inflammatory metabolite adenosine that can additionally be taken in by the worms as food. We envision the tegumental ectonucleotidases as having a twofold role at the worm surface: first, they degrade potentially harmful host signaling molecules, and second, they generate vital nutrients around the worms from where these can be conveniently imported.

Infection with intravascular platyhelminths of the genus Schistosoma can result in the debilitating disease schistosomiasis. Schistosomes (blood flukes) can survive in the host for many years. We hypothesize that proteins on their host-interactive surface modify the worm’s external environment to help insure worm survival. Previously, we have shown that a surface ectoenzyme of Schistosoma mansoni, SmNPP5 – a nucleotide pyrophosphatase/phosphodiesterase – can cleave ADP and block platelet aggregation in vitro. In this work, we show that both adult schistosomes and recombinant SmNPP5 can cleave the exogenous purinergic signaling molecule nicotinamide adenine dinucleotide (NAD). In doing so, worms and rSmNPP5 can prevent NAD-induced apoptosis of T cells in vitro. Since regulatory T cells (Tregs) are especially prone to such NAD-induced cell death (NICD), we hypothesize that schistosome cleavage of NAD promotes Treg survival which creates a more immunologically hospitable environment for the worms in vivo. In addition to SmNPP5, schistosomes express another host-interactive NAD-degrading enzyme, SmNACE. We successfully suppressed the expression of SmNPP5 and SmNACE (singly or together) using RNAi. Only SmNPP5-suppressed worms, and not SmNACE-suppressed worms, were significantly impaired in their ability to cleave exogenous NAD compared to controls. Therefore, we contend that ectoenzyme SmNPP5 on the surface of the worm is primarily responsible for extracellular NAD cleavage and that this helps modulate the host immune environment by preventing Treg cell death.