CONICET | Buscador de Institutos y Recursos Humanos

Expression of the membrane-bound efflux pump P-glycoprotein (Pgp) is associated with the phenomenon of multidrug-resistance in pathogenic organisms, including protozoan and helminth parasites, but the role in physiological processes remains limited. Studies based on efflux analyses in the presence of P-gp substrates (calcein-AM) suggested that an active P-gp is present in Echinococcus granulosus (Eg), an important human pathogen, causing cystic echinococcosis (hydatidosis). In support, studies of confocal microscopy and immunohistochemistry showed that Eg-Pgp was localized in the structures adapted for absorption-excretion functions, as tegument and suckers. In this study, this ABC transporter has been identified in protoscoleces and metacestodes by sequencing and molecular cloning (GenBank Accession Number HM590698), and shown a typical P-gp structure (P-loop NTPasas). In addition, the genome of E. multilocularis revealed the presence of the same orthologous gene with approx. 1280 residues, 4 exons and possible alternative splicing. On the other hand, we investigated the effects of possible P-gp inhibitors (trifluoperazine, loperamide and tamoxifen) in the viability of Eg. We demonstrated that these FDA-approved drugs, as calcium channel activators and/or potent calmodulin inhibitors, provoke increased the intracellular calcium levels, induced autophagic degradation and inhibited parasite viability in the larval forms (protoscoleces and metacestodes) as described in other biological systems (Zhang et al.,2007). But all above, they can act as potent blockers of Eg-Pgp. Therefore, these results suggest a crucial role of calcium homeostasis as essential processes in Eg and further validate the potential of P-gp inhibitors as a target for drug development. Further investigations of a potential role of P-gp in Ca2+-mediated processes, could reveal the effect of P-gp inhibitors in cellular mechanisms which depend on Ca2+ signaling in the parasite.

enviar mensaje