Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure

Abstract

Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since PZQ’s half-life is ~2 hours in humans and ~30 minutes in mice, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate/humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy.

Long Non-Coding RNA Levels Are Modulated in Schistosoma mansoni following In Vivo Praziquantel Exposure

“…In this study, we demonstrate that in vivo exposure to PZQ induces significant changes in the expression of the worm's lncRNAs, even several hours after the treatment. In our re-analyses of the RNA-Seq data of McCusker et al [11], we found hundreds of lncRNAs differentially expressed both in mature and immature worms. Through RT-qPCR we validated the differential expression of selected lncRNAs, underscoring the impact of PZQ on altering S. mansoni lncRNA expression.…”

“…Nevertheless, worm response to this drug is still not fully understood since it depends on a complex disruption of the parasite homeostasis. This involves the host's immune system [1,6,7] in addition to the regulation of gene expression in the parasite when exposed to PZQ, as shown by McCusker et al [11].…”

“…Given the intricate nature of schistosomes' response to PZQ [6,11], which remains incompletely understood, and recognizing the significant functions and regulatory roles exhibited by S. mansoni lncRNAs [24], we hypothesized that S. mansoni lncRNAs could be involved in parasite response following in vivo PZQ exposure. In this study, we demonstrate that in vivo exposure to PZQ induces significant changes in the expression of the worm's lncRNAs, even several hours after the treatment.…”

Immunomodulating Potential of Ekebergia capensis in Murine Schistosoma mansoni Juvenile and Adult Infection

“…PZQ's lack of efficacy in immature worms may be a result of the need for involvement of the hosts' immune system since eggs are released by sexually mature worms and the host responds to their antigens with a wave of macrophage recruitment to the liver and an acute Th2 response [62], [63]. A study by McCusker et al reported that in vivo exposure to PZQ resulted in the alteration of the transcription gene products of S. mansoni [64].…”

Translating From Egg- to Antigen-Based Indicators for Schistosoma mansoni Elimination Targets: A Bayesian Latent Class Analysis Study

“…This is most likely due to the number of eggs being excreted per adult worm present, changing with treatment. This could also be due to juvenile worms surviving treatment and continuing to regurgitate antigens but not yet producing eggs, or previously egg-producing adult worms surviving treatment but becoming - at the very least, temporarilysterilized (26) or otherwise unable to reproduce (27).…”