Transcriptional analysis of Schistosoma mansoni treated with praziquantel in vitro

Abstract

Schistosomiasis is one of the foremost health problems in developing countries and has been estimated to account for the loss of up to 56 million annual disability-adjusted life years. Control of the disease relies almost exclusively on praziquantel (PZQ) but this drug does not kill juvenile worms during the early stages of infection or prevent post-treatment reinfection. As the use of PZQ continues to grow, there are fears that drug resistance may become problematic thus there is a need to develop a new generation of more broadly effective anti-schistosomal drugs, a task that will be made easier by having an understanding of why PZQ kills sexually mature worms but fails to kill juveniles. Here, we describe the exposure of mixed-sex juvenile and sexually mature male and female Schistosoma mansoni to 1 μg/mL PZQ in vitro and the use of microarrays to observe changes to the transcriptome associated with drug treatment. Although there was no significant difference in the total number of genes expressed by adult and juvenile schistosomes after treatment, juveniles differentially regulated a greater proportion of their genes. These included genes encoding multiple drug transporter as well as calcium regulatory, stress and apoptosis-related proteins. We propose that it is the greater transcriptomic flexibility of juvenile schistosomes that allows them to respond to and survive exposure to PZQ in vivo.

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

“…Three of these (HSP70, ferritin and thioredoxin peroxidase 1) were selected (Fig 9K–9M) as we observed previously that exposure of S . mansoni to PZQ results in induction of these stress response genes [17, 22]. This observation was broadly repeated in this study, with all 3 genes being induced significantly in juveniles with ferritin and thioredoxin peroxidase 1 being induced significantly in adult after four days of treatment suggesting that both juveniles and adults were still alive at this time.…”

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…Furthermore, SMRD2 is modulated by PZQ1, suggesting that PZQ1 is also a substrate for SMRD2 (119). Transcriptomic analysis reveals increasing levels of transcripts encoding the ABC transporters SMDR1, SmMRP1, SmMRD2, and SMDR3 in juveniles exposed to PZQ1 in vitro, supporting the notion that ABC transporters participate in resistance to PZQ1 in schistosomes (75). Guglielmo et al (120) developed a series of PZQ NO-donors furoxans that are worthy of investigation in view of their potential activity against PZQ-resistant schistosomes.…”

“…High-throughput transcriptomic approaches have been employed to address the refractory/susceptible nature of the developmental stages of schistosomes in terms of PZQ1 activity (73)(74)(75)(76)(77). These studies revealing genes that might be evolved in aerobic metabolism and cytosolic calcium regulation, suggesting that schistosomes undergo a transcriptomic response similar to that seen during oxidative stress (74).…”

New approaches for understanding mechanisms of drug resistance in schistosomes

“…For example, the juvenile worms that are refractory to PZQ still undergo a Ca 2+ -dependent contraction and paralysis similar to that observed in adult worms (Pica-Mattoccia et al 2008). Unlike adults, however, juveniles recover and survive, indicating that though the initial target is likely similar, adaptive responses that allow parasite survival come into play in the immature, but not mature, worms (Hines-Kay et al 2012). …”