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

Abstract

Schistosomiasis is a chronic parasitic disease caused by sexually dimorphic blood flukes of the genus Schistosoma. 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 Schistosoma mansoni 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 S. mansoni genes during infection and their response to Vh and PZQ treatment in vivo. 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.

Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models

“…Our present study now reconcile such observations, demonstrating that PZQ has potential preventive antifibrotic effects while it has no efficacy in therapeutically reversing established fibrosis. This conclusion reliably recapitulates the established view of most authors on the subject 9,11,21,[53][54][55][56][57][58][59][60][61][62][63] where PZQ antifibrotic / anti-pathological potential in clinically fibrotic schistosomiasis-diseased patients might not be direct and/or effective on established fibrosis but entirely consequent to its anti-parasitic effect when administered after fibrosis development.…”

“…The extensive usage of PZQ during mass drug administration campaigns in flatworm-endemic areas has considerable health benefits for the target populations over time such as improved fitness, improved cognitive functions and reduced tissue fibrosis 13,[15][16][17][18][19][20]34,[40][41][42][43][44][45][46][47][48][49][50][51][52] . Whereas most authors associated such health benefits and particularly the improvement of tissue fibrosis in helminth-infested individuals to the sole antiparasitic potential of PZQ 9,11,21,[53][54][55][56][57][58][59][60][61][62][63] , recent reports on the drug ability to also directly mitigate tissue fibrosis have also emerged 13,[15][16][17][18][19][20]34,[40][41][42][43]…”

Effects of the Environment on Developmental Plasticity and Infection Success of Schistosoma Parasites – An Epigenetic Perspective

“…Details on immunology of human schistosomiasis were reviewed recently (Colley and Secor, 2014). Briefly, from the first moments after cercarial infection to the end of worm maturation in the blood stream, Th1-type immune responses against schistosomulae result in noticeable increase in certain cytokines (TNFα, IL1α, IL1β, and IL6) as well as Signal Transducers, Activators of Transcription 1 (STAT1), and IFNγ (Burke et al, 2009, 2010; Sanchez et al, 2017). However, once adult worms start depositing eggs around 6 weeks after initial infection, a dramatic shift to a Th2-type immune response ensues.…”

Identification of 170 New Long Noncoding RNAs in Schistosoma mansoni

“…In this study, we aimed to predict novel lncRNAs in S. mansoni via a computational pipeline and investigate features including possible functions of these sequences. Here we describe a complete new set of 170 lncRNAs in adult worms, from which we selected 15 for expression analysis in male, female, and also, for the first time, praziquantel-resistant worms which are known to have a differential expression profile in several important genes in relation to susceptible worms [ 8 , 22 , 23 ]. Our results show a differential expression profile of lncRNAs and reinforce the importance of this RNA subtype in schistosome biology.…”