Flavone resistant Leishmania donovani over expresses LdMRP2 transporter in the parasite and activates host MRP2 on macrophages to circumvent the flavone-mediated cell death [Molecular Bases of Disease]

April 4th, 2014 by Chowdhury, S., Mukhopadhyay, R., Saha, S., Mishra, A., Sengupta, S., Roy, S., Majumder, H. K.

In parasites, ATP binding cassette (ABC) transporters represent an important family of proteins related to drug resistance and other biological activities. Resistance of leishmanial parasites to therapeutic drugs continues to escalate in developing countries and in many instances it is due to overexpressed ABC efflux pumps. Progressively adapted baicalein (BLN)resistant parasites (pB25R) show overexpression of a novel ABC transporter, which was classified as ABCC2 or LdMrp2. The protein is primarily localized in the flagellar pocket region and in internal vesicles. Overexpressed LdABCC2 confers substantial BLN resistance to the parasites by rapid drug efflux. The BLN-resistant promastigotes when transformed into amastigotes in macrophage cells cannot be cured by treatment of macrophages with BLN. Amastigotes resistance is concomitant to the over expression of macrophage multidrug resistance protein 2 (MRP2) transporter. Reporter analysis and site directed mutagenesis assays demonstrate that antioxidant response element (ARE) 1 is activated upon infection. The expression of this phase II detoxifying gene is regulated by Nrf2 (NFE2 related factor 2) mediated antioxidant response element (ARE) activation. In view of the fact that the signaling pathway of phospho inositol 3 kinase controls microfilament rearrangement and translocation of actin associated proteins, the current study correlates with intricate pathway of PI3 kinase mediated nuclear translocation of Nrf2 which activates Mrp2 expression in macrophages upon infection by the parasites. In contrast, phalloidin, an agent that prevents actin filaments from depolymerization, inhibits Nrf2 translocation and Mrp2 activation by pB25R infection. Taken together, these results provide an insight into the mechanisms by which resistant clinical isolates of Leishmania donovani induce intracellular events relevant to drug resistance.
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