Effect of Praziquantel on Schistosoma mekongi Proteome and Phosphoproteome.

Peerut Chienwichai,Sumate Ampawong,Tipparat Thiangtrongjit,Yanin Limpanont,Phiraphol Chusongsang,Poom Adisakwattana,Yupa Chusongsang,Onrapak Reamtong

doi:10.3390/pathogens9060417

Abstract

Schistosoma mekongi causes schistosomiasis in southeast Asia, against which praziquantel (PZQ) is the only treatment option. PZQ resistance has been reported, thus increasing the requirement to understand mechanism of PZQ. Herein, this study aimed to assess differences in proteome and phosphoproteome of S. mekongi after PZQ treatment for elucidating its action. Furthermore, key kinases related to PZQ effects were predicted to identify alternative targets for novel drug development. Proteomes of S. mekongi were profiled after PZQ treatment at half maximal inhibitory concentration and compared with untreated worms. A total of 144 proteins were differentially expressed after treatment. In parallel, immunohistochemistry indicated a reduction of phosphorylation, with 43 phosphoproteins showing reduced phosphorylation, as identified by phosphoproteomic approach. Pathway analysis of mass spectrometric data showed that calcium homeostasis, worm antigen, and oxidative stress pathways were influenced by PZQ treatment. Interestingly, two novel mechanisms related to protein folding and proteolysis through endoplasmic reticulum-associated degradation pathways were indicated as a parasiticidal mechanism of PZQ. According to kinase–substrate predictions with bioinformatic tools, Src kinase was highlighted as the major kinase related to the alteration of phosphorylation by PZQ. Interfering with these pathways or applying Src kinase inhibitors could be alternative approaches for further antischistosomal drug development.

Highlights

Schistosomiasis, known as bilharzia, is a neglected tropical disease that infects over 200 million people worldwide each year, resulting in 200,000 deaths [1,2]
To examine the effective dose of PZQ for parasiticide activity on S. mekongi, adult worms were exposed to various concentrations of PZQ for 60 min and worm viability was assessed by observing the movement of the worms under a video microscope
Worms treated with 40 μg/mL-PZQ were further investigated for protein expression alteration

Summary

Introduction

Schistosomiasis, known as bilharzia, is a neglected tropical disease that infects over 200 million people worldwide each year, resulting in 200,000 deaths [1,2]. The only drug currently available for the treatment and prevention of S. mekongi is praziquantel (PZQ) [7,8]. PZQ has long been considered the drug of choice for schistosomiasis [7]. It has been extensively used for the treatment and control of blood fluke infections and other parasitic diseases for both medical and veterinary purposes [7,9]. PZQ shows excellent efficacy against various species of worm; drug resistance and low susceptibility of parasites have been recently observed [10,11]. PZQ resistance has been reported in various species of worms, including

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