Schistosoma mansoni P-glycoprotein levels increase in response to praziquantel exposure and correlate with reduced praziquantel susceptibility

Abstract

One potential physiological target for new antischistosomals is the parasite's system for excretion of wastes and xenobiotics. P-glycoprotein (Pgp), a member of the ATP-binding cassette superfamily of proteins, is an ATP-dependent efflux pump involved in transport of toxins and xenobiotics from cells. In vertebrates, increased expression of Pgp is associated with multidrug resistance in tumor cells. Pgp may also play a role in drug resistance in helminths. In this report, we examine the relationship between praziquantel (PZQ), the current drug of choice against schistosomiasis, and Pgp expression in Schistosoma mansoni. We show that levels of RNA for SMDR2, a Pgp homolog from S. mansoni, increase transiently in adult male worms following exposure to sublethal concentrations (100 -500 nM) of PZQ. A corresponding, though delayed, increase in anti-Pgp immunoreactive protein expression occurs in adult males following exposure to PZQ. The level of anti-Pgp immunoreactivity in particular regions of adult worms also increases in response to PZQ. Adult worms from an Egyptian S. mansoni isolate with reduced sensitivity to PZQ express increased levels of SMDR2 RNA and anti-Pgp-immunoreactive protein, perhaps indicating a role for multidrug resistance proteins in development or maintenance of PZQ resistance.

Parasite annexins – New molecules with potential for drug and vaccine development

“…By contrast, resistance in hookworms to the anthelminthic pyrantel appears to be regulated through variable transcriptional regulation of multiple family members of drug-sensitive molecules, in this case of different nicotinic acetylcholine receptor subunits [82]. Similar variable transcription of P-glycoproteins is central to insensitivity in schistosomes to the anti-schistosomal drug praziquantel [83,84]. Interestingly, both genetic polymorphism and transcriptional variation have been postulated to explain why a recombinant vaccine designed against a schistosome tetraspanin was ineffective in experimental schistosomiasis japonica, while efficacious in schistosomiasis mansoni [85,86].…”

Sex in Schistosomes – Signaling Mechanisms in the Female Gonads

“…The understanding of the cellular processes during gonad differentiation and the identification of molecules controlling these processes contribute to our knowledge about the unusual biology of this parasite, thus providing a promising starting point for the development of new strategies to fight schistosomes. In the light of first studies describing the emergence of partial resistance to Praziquantel (Botros et al 2005;Cioli and Pica-Mattoccia 2003;Doenhoff et al 2008;Kusel and Hagan 1999;Melman et al 2009;Messerli et al 2009;Pica-Mattoccia et al 2009), and due to the fact that there is still no vaccine available ready to use, there is an urgent need for the development of alternative medication.…”

“…About 85% of infected people live in sub-Saharan Africa, where the number of deaths was estimated at 200,000 per year (Engels et al 2002). In the light of accumulating evidence from experimental and field studies for resistance against the commonly used drug Praziquantel (PZQ) (Botros et al 2005;Doenhoff et al 2008;Melman et al 2009;Messerli et al 2009;Pica-Mattoccia et al 2009), and since no vaccine is available yet (McManus and Loukas 2008), great international research efforts have been initiated by governmental and educational institutions, industry, and WHO programs. Their aims are to create innovative ideas with the potential to be translated into safe, effective, affordable and widely utilized interventions to protect against this parasite.…”

Molecular cloning and characterization of a gene encoding methionine aminopeptidase 2 of Schistosoma japonicum

“…Praziquantel is a pyrazinoisoquinoline derivative that is effective against almost all species of schistosome. However, the prospect of emerging resistance to praziquantel has stimulated attempts to identify new drug targets or vaccine candidates by increased investigation of the biological and molecular aspects of this parasite (Messerli et al 2009;Wang et al 2009). …”