title: TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to the inhibition of P. falciparum growth in human blood.
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.
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: I
authors.initials: I
authors.lastname: Marginedas-Freixa
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Hattab
authors.affiliation: UMR 8227 Comparative Erythrocyte's Physiology, CNRS, Université Pierre et Marie Curie, Sorbonne Universités, Laboratoire d'Excellence GR-Ex, F-29680 Roscoff, France.
authors.forename: G
authors.initials: G
authors.lastname: Bouyer
authors.affiliation: UMR7200, Faculty of Pharmacy, University of Strasbourg, CNRS, 67400 Illkirch Graffenstaden, France.
authors.forename: F
authors.initials: F
authors.lastname: Halle
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Chene
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: S D
authors.initials: SD
authors.lastname: Lefevre
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Cambot
authors.affiliation: UMR 8227 Comparative Erythrocyte's Physiology, CNRS, Université Pierre et Marie Curie, Sorbonne Universités, Laboratoire d'Excellence GR-Ex, F-29680 Roscoff, France.
authors.forename: A
authors.initials: A
authors.lastname: Cueff
authors.affiliation: UMR7200, Faculty of Pharmacy, University of Strasbourg, CNRS, 67400 Illkirch Graffenstaden, France.
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Gamain
authors.affiliation: UMR 7203 LBM, CNRS, Université Pierre et Marie Curie, Sorbonne Universités, École Normale Supérieure - PSL Research University, Département de Chimie. F-75005 Paris, France.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lacapere
authors.affiliation: UMR 8227 Comparative Erythrocyte's Physiology, CNRS, Université Pierre et Marie Curie, Sorbonne Universités, Laboratoire d'Excellence GR-Ex, F-29680 Roscoff, France.
authors.forename: S
authors.initials: S
authors.lastname: Egee
authors.affiliation: UMR7200, Faculty of Pharmacy, University of Strasbourg, CNRS, 67400 Illkirch Graffenstaden, France.
authors.forename: F
authors.initials: F
authors.lastname: Bihel
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Van Kim
authors.affiliation: UMR_S1134, Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris, France.
authors.forename: M A
authors.initials: MA
authors.lastname: Ostuni
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001692:Biological Transport; D002454:Cell Differentiation; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008024:Ligands; D013058:Mass Spectrometry; D010271:Parasites / Q000254:growth & development; D010963:Plasmodium falciparum / Q000254:growth & development*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018079:Receptors, GABA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050994:Voltage-Dependent Anion Channels / Q000737:chemistry / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D008024:Ligands; D020033:Protein Isoforms; D011524:Protoporphyrins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018079:Receptors, GABA; C499229:TSPO protein, human; D050994:Voltage-Dependent Anion Channels; C017803:zinc protoporphyrin; D005978:Glutathione