TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to the inhibition of P. falciparum growth in human blood.

I Marginedas-Freixa,C Le Van Kim,S Egee,B Gamain,M Cambot,M A Ostuni,F Bihel,S D Lefevre,A Cueff,G Bouyer,A Chene,J J Lacapere,M Schmitt,F Halle,C Hattab

doi:10.1038/srep33516

Abstract

After invading red blood cells (RBCs), Plasmodium falciparum (Pf) can export its own proteins to the host membrane and activate endogenous channels that are present in the membrane of RBCs. This transport pathway involves the Voltage Dependent Anion Channel (VDAC). Moreover, ligands of the VDAC partner TranSlocator PrOtein (TSPO) were demonstrated to inhibit the growth of the parasite. We studied the expression of TSPO and VDAC isoforms in late erythroid precursors, examined the presence of these proteins in membranes of non-infected and infected human RBCs, and evaluated the efficiency of TSPO ligands in inhibiting plasmodium growth, transporting the haem analogue Zn-protoporphyrin-IX (ZnPPIX) and enhancing the accumulation of reactive oxygen species (ROS). TSPO and VDAC isoforms are differentially expressed on erythroid cells in late differentiation states. TSPO2 and VDAC are present in the membranes of mature RBCs in a unique protein complex that changes the affinity of TSPO ligands after Pf infection. TSPO ligands dose-dependently inhibited parasite growth, and this inhibition was correlated to ZnPPIX uptake and ROS accumulation in the infected RBCs. Our results demonstrate that TSPO ligands can induce Pf death by increasing the uptake of porphyrins through a TSPO2–VDAC complex, which leads to an accumulation of ROS.

Highlights

I Marginedas-Freixa, C Hattab, G Bouyer, F Halle, A Chene, et al
The reactive oxygen species (ROS) peak was reached only 12 h after the addition of the ligands. These results demonstrated that TranSlocator PrOtein (TSPO) ligands induced a constitutive ROS accumulation in both hRBCs and Infected RBCs (iRBCs) and that this phenomenon was accelerated by the presence of ZnPPIX
Only TSPO1 was identified as a mitochondrial outer membrane protein involved in different functions that could be modulated by specific TSPO ligands

Summary

Introduction

I Marginedas-Freixa, C Hattab, G Bouyer, F Halle, A Chene, et al. TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to the inhibition of P. falciparum growth in human blood. We studied the expression of TSPO and VDAC isoforms in late erythroid precursors, examined the presence of these proteins in membranes of non-infected and infected human RBCs, and evaluated the efficiency of TSPO ligands in inhibiting plasmodium growth, transporting the haem analogue Znprotoporphyrin-IX (ZnPPIX) and enhancing the accumulation of reactive oxygen species (ROS). TSPO ligands dose-dependently inhibited parasite growth, and this inhibition was correlated to ZnPPIX uptake and ROS accumulation in the infected RBCs. Our results demonstrate that TSPO ligands can induce Pf death by increasing the uptake of porphyrins through a TSPO2–VDAC complex, which leads to an accumulation of ROS. It remains a major public health problem in developing countries worldwide, resulting in approximately 200 million new infections per year and more than 500,000 subsequent deaths[1]

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