The anthelmintic praziquantel is a human serotoninergic G-protein-coupled receptor ligand

Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer - (R)-PZQ - which functions as a partial agonist of the human serotoninergic 5HT2B receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite

Praziquantel sensitivity of Kenyan Schistosoma mansoni isolates and the generation of a laboratory strain with reduced susceptibility to the drug

Schistosomiasis is a neglected tropical disease caused by blood-dwelling flukes of the genus Schistosoma. While the disease may affect as many as 249 million people, treatment largely relies on a single drug, praziquantel. The near exclusive use of this drug for such a prevalent disease has led to concerns regarding the potential for drug resistance to arise and the effect this would have on affected populations. In this study, we use an in vitro assay of drug sensitivity to test the effect of praziquantel on miracidia hatched from eggs obtained from fecal samples of Kenyan adult car washers and sand harvesters as well as school children. Whereas in a previous study we found the car washers and sand harvesters to harbor Schistosoma mansoni with reduced praziquantel sensitivity, we found no evidence for the presence of such strains in any of the groups tested here. Using miracidia derived from seven car washers to infect snails, we used the shed cercariae to establish a strain of S. mansoni with significantly reduced praziquantel sensitivity in mice. This was achieved within 5 generations by administering increasing doses of praziquantel to the infected mice until the parasites could withstand a normally lethal dose. This result indicates that while the threat of praziquantel resistance may have diminished in the Kenyan populations tested here, there is a strong likelihood it could return if sufficient praziquantel pressure is applied

Effect of praziquantel on the differential expression of mouse hepatic genes and parasite ATP binding cassette transporter gene family members during <i>Schistosoma mansoni</i> infection

<div><p>Schistosomiasis is a chronic parasitic disease caused by sexually dimorphic blood flukes of the genus <i>Schistosoma</i>. Praziquantel (PZQ) is the only drug widely available to treat the disease but does not kill juvenile parasites. Here we report the use of next generation sequencing to study the transcriptional effect of PZQ on murine hepatic inflammatory, immune and fibrotic responses to <i>Schistosoma mansoni</i> worms and eggs. An initial T helper cell 1 (Th1) response is induced against schistosomes in mice treated with drug vehicle (Vh) around the time egg laying begins, followed by a T helper cell 2 (Th2) response and the induction of genes whose action leads to granuloma formation and fibrosis. When PZQ is administered at this time, there is a significant reduction in egg burden yet the hepatic Th1, Th2 and fibrotic responses are still observed in the absence of granuloma formation suggesting some degree of gene regulation may be induced by antigens released from the dying adult worms. Quantitative real-time PCR was used to examine the relative expression of 16 juvenile and adult <i>S</i>. <i>mansoni</i> genes during infection and their response to Vh and PZQ treatment <i>in vivo</i>. While the response of stress genes in adult parasites suggests the worms were alive immediately following exposure to PZQ, they were unable to induce transcription of any of the 9 genes encoding ATP-binding cassette (ABC) transporters tested. In contrast, juvenile schistosomes were able to significantly induce the activities of ABCB, C and G family members, underscoring the possibility that these efflux systems play a major role in drug resistance.</p></div

Canonical pathway analysis of T helper cell maturation and differentiation in PZQ treated infected mice.

<p>Signaling events in the T cell maturation and differentiation pathway at (A) 32, (B) 35, (C) 39 and (D) 46 days in infected PZQ (Sm_PZQ) treated mice. Increasing expression in infected mice relative to uninfected mice is indicated by deeper blue shading. None of the genes indicated were down-regulated. Non-expression and non-differential expression is indicated by a lack of shading.</p

Temporal expression of mouse hepatic genes during infection with <i>S</i>. <i>mansoni</i>.

<p>Heat maps of (A) immune and (B) fibrotic gene markers depicting differentially expressed genes in infected Vh and PZQ treated mice relative to uninfected mice. Gray map sections represent genes not expressed at that time point or in that treatment group. Regions of blue and red indicate, relative to uninfected Vh treated controls, increased and decreased gene expression respectively. The color scale indicates log₂ fold change (FC) and the profile of each group is the average of three biological replicates. Gene names associated with the figure differ slightly from those used in the text. Relevant differences include: Ccl (rather than CCL as it appears in the main body of text), Cxc (CXC), Cxcl (CXCL), Il1b (IL1β), Tnfa (TNFα), Tgfb (TGFβ), Ifng (IFNγ), Cd (CD) and Timp (TIMP).</p

The effects of PZQ on infected host liver.

<p>(A) Effect of treatment with Vh and PZQ on the number of parasites present in host livers at days 32, 35 and 46 post infection, n = 5 per treatment group. (B) Number of parasite eggs per gram of liver at days 32, 35, 39 and 46 post infection after treatment with Vh and PZQ (n = 4). (C) Weight of liver at days 32, 35, 39 and 46 post infection after treatment with Vh and PZQ (n = 4). Error bars represent mean with standard deviation. * p <0.05 and *** p < 0.001.</p

Canonical pathway analysis of hepatic fibrosis and stellate cell activation in PZQ treated infected mice.

<p>Signaling events in the fibrotic and stellate cell activation pathway at (A) 32, (B) 35, (C) 39 and (D) 46 days post infection in infected PZQ (Sm_PZQ) treated mice. Increasing expression in infected mice relative to uninfected mice is indicated by deeper blue shading. Decreased expression is shown in dark red. Non-expression and non-differential expression is indicated by a lack of shading.</p