Purinergic signaling in schistosomal infection

Abstract

Human schistosomiasis is a chronic inflammatory disease caused by blood fluke worms belonging to the genus Schistosoma. Health metrics indicate that the disease is related to an elevated number of years lost-to-disability and years lost-to-life. Schistosomiasis is an intravascular disease that is related to a Th1 and Th2 immune response polarization, and the degree of polarization affects the outcome of the disease. The purinergic system is composed of adenosine and nucleotides acting as key messenger molecules. Moreover, nucleotide-transforming enzymes and cell-surface purinergic receptors are obligatory partners of this purinergic signaling. In mammalian cells, purinergic signaling modulates innate immune responses and inflammation among other functions; conversely purinergic signaling may also be modulated by inflammatory mediators. Moreover, schistosomes also express some enzymes of the purinergic system, and it is possible that worms modulate host purinergic signaling. Current data obtained in murine models of schistosomiasis support the notion that the host purinergic system is altered by the disease. The dysfunction of adenosine receptors, metabotropic P2Y and ionotropic P2X₇ receptors, and NTPDases likely contributes to disease morbidity.

Keywords: Endothelial cell; Inflammation; Macrophages; NTPDases; Purinergic receptor; Schistosomiasis.

Fig. 1

Illustrated schematic of the Schistosoma lifecycle. Infected snails (D) release the larval form cercariae (E) in a body of water. Human schistosomiasis starts after the cercariae penetration the skin in direction to a venule or lymphatic vessel (A). The worms navigate through the cardiovascular system reaching vessels from the gut (S. mansoni and S. japonicum) or bladder (S. hematobium). Adult worms mate, and females lay hundreds of eggs daily (B). The eggs release miracidium in the water (C), which is infective for snails. The asexual reproduction of a miracidium generates several cercariae that are released via the snail. Adult male worms are about 1 cm long. They have smooth muscle layers beneath the external tegument and two suckers by which they attach to the blood vessel wall.

Fig. 2

Purinergic receptors. Extracellular nucleotides mediate intracellular signaling through cell surface ionotropic ATP-gated receptors (P2X) and metabotropic P2Y receptors. On the other hand, adenosine receptors (A) are activated by adenosine (Ado). The conversion of ATP to other nucleotides and adenosine is mediated by ecto-enzymes .

Fig. 3

Survival curves of S. mansoni-infected mice (black line: C57BL/6 wild type; Red line: P2X₇ receptor knockout mice (P2X₇RKO)). Newborn mice were infected and observed for 9 weeks.