Transcriptomic analysis of reduced sensitivity to praziquantel in Schistosoma mansoni

Abstract

Schistosomiasis is an intravascular parasitic infection estimated to affect over 206 million people, the majority of whom live in Africa where the trematode worms Schistosoma mansoni and Schistosoma haematobium are the major causative agents. While a number of drugs have been used to treat schistosomiasis, praziquantel (PZQ) is the only one that is widely available, relatively cheap, and easy to use. The reliance on a single drug for the treatment of such a prevalent disease is a cause for concern due to the potential for resistance to render PZQ ineffective. In this study, we examine the transcriptome of three generations of a laboratory strain of S. mansoni (PR1) whose susceptibility to PZQ has been diminished across 9 passages through exposure to increasing sub-lethal doses of the drug. Miracidial susceptibility was significantly reduced after exposure to 2 × 50 mg/Kg PZQ during the first passage. Susceptibility of worms in vivo was first assessed during passage 5 when mice infected with PZQ-selected schistosomes were dosed with a lethal dose of 3 × 300 mg/kg PZQ resulting in only a 10% reduction in worm number compared to control treatment. The emergence of reduced sensitivity was marked by a shift in sex ratio from a predominantly male to a female population, a reduction in the length of females and ultimately the loss of the PZQ-selected line after passage 9. Analysis of differentially regulated transcripts did not suggest that any particular gene product or pathway was associated with drug resistance suggesting either a loss of function mutation to a single gene or an epistatic interaction of multiple gene products as the underlying cause of reduced susceptibility.

Effect of Praziquantel on Schistosoma mekongi Proteome and Phosphoproteome

“…Our study found altered expression of the same protein or proteins with similar function; heat shock protein 70 (O45039) and sodium/potassium-transporting ATPase subunit alpha (A0A095AFH4, A0A094ZR23) ( Table S1 ,2). Furthermore, gene expression profiling of less-susceptible parasite indicated a list of gene involving with calcium signaling pathway (calcium binding protein, calmodulin, calponin) and oxidative stress response (thioredoxin and superoxide dismutase) [ 36 ]. Our mass spectrometric data also found proteins in those pathways, which were 20 kDa calcium-binding protein (A0A095A3D3), putative annexin (G4VL68), voltage-dependent anion-selective channel protein (VDAC) (G4M1U8) for calcium signaling pathway and tryparedoxin peroxidase (C1LV40), glutathione-S-transferase (Q26513) for oxidative stress pathway ( Table 5 ).…”

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

“…We suspect that standing variation for PZQ resistance is also likely, because this trait is easy to select in the laboratory. This has been done by several groups using independent laboratory populations, and resistance has spread within very few generations [49–54], strongly suggesting that resistance alleles were already present in these laboratory populations. Furthermore, the laboratory populations used for selection were isolated before PZQ was available [23,55] and so were not exposed to drug selection.…”

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

“…Kunitz-type protease inhibitors have also been found in the secretomes of other parasitic flatworms [62,63], and shown to act as ion channel blockers [64] and inhibitors of dendritic cell activation [65]. Additionally, laboratory strains of S. mansoni selected for PZQ resistance show altered expression of a various Kunitz-type protease inhibitors, indicating these may be involved in drug resistance [42].…”