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Antimalarial Chemotherapy pp 27–41Cite as

Transport and Trafficking in Plasmodium-Infected Red Cells

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Part of the book series: Infectious Disease ((ID))

Abstract

The organism at the focus of antimalarial chemotherapy is Plasmodium falciparum. It causes the most virulent of human malarias and shows rapidly emerging drug resistance. The main targets of antimalarials are blood-stage parasites that are responsible for all of the symptoms and pathologies associated with the disease. These stages reside in the mature erythrocyte, a terminally differentiated, simple, host cell that is devoid of all intracellular organelles and are surrounded by a parasitophorous vacuolar membrane (PVM: see Fig. 1). The host erythrocyte is incapable of de novo protein or lipid synthesis and does not engage in the internalization of its surface membrane (1). There is a complete lack of endocytic machinery, which is lost as the reticulocyte matures into the erythrocyte. Hence, antimalarials need to enter an unusual intracellular niche.

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References

  1. Chasis JA, Prenant M, Leung A, Mohandas N. Membrane assembly and remodelling during reticulocyte maturation. Blood 1989; 74: 1112–1120.

    PubMed  CAS  Google Scholar 

  2. Desai SA, Krogstad DJ, McCleskey EW. A nutrient-permeable channel on the intraerythrocytic malaria parasite. Nature 1993; 362: 643–646.

    Article  PubMed  CAS  Google Scholar 

  3. Kirk K, Homer HA, Elford BC, Ellory JC, Newbold C. Transport of diverse substrates into malaria infected erythrocytes via pathway showing functional characteristics of a chloride channel. Biol J Chem 1994; 269: 3339–3347.

    CAS  Google Scholar 

  4. Lauer SA, Rathod PK, Ghori N, Haldar K. A membrane network for nutrient import in red cells infected with the malaria parasite. Science 1997; 276: 1122–1125.

    Article  PubMed  CAS  Google Scholar 

  5. Akompong T, VanWye J, Ghori N, Haldar K. Artemisinin and its derivatives are transported by a vacuolar network of P. falciparum and their anti-malarial activities are additive with toxic sphingolipid analogues that block the network. Mol Biochem Parasitol 1999; 100: 71–79.

    Article  Google Scholar 

  6. Kirk K, Homer HA. In search of a selective inhibitor of the induced transport of small solutes in Plasmodium falciparum-infected erythrocytes: effects of arylaminobenzoates. Biochem J 1995; 311: 761–768.

    PubMed  CAS  Google Scholar 

  7. Lauer S, Ghori N, Haldar K. Sphingolipid synthesis as a novel target for chemotherapy against malaria parasites. Proc Natl Acad Sci USA 1995; 92: 9181–9185.

    Article  PubMed  CAS  Google Scholar 

  8. Blackman MJ, Scott-Finnigan TJ, Shai S, Holder AA. Antibodies inhibit the protease-mediated processing of a malaria merozoite surface protein. J Exp Med 1994; 180: 389–393.

    Article  PubMed  CAS  Google Scholar 

  9. Elford BC, Cowman GM, Ferguson DJP. Parasite regulated membrane transport processes and metabolic control in malaria-infected erythrocytes. Biochem J 1995; 308: 361–374.

    PubMed  CAS  Google Scholar 

  10. Haldar K, Holder AA. Export of parasite proteins to the erythrocyte in Plasmodium falciparum-infected cells. Semin Cell Biol 1993; 4: 345–353.

    Article  PubMed  CAS  Google Scholar 

  11. Deitsch KW, Wellems TE. Membrane modifications in erythrocytes parasitized by Plasmodium falciparum. Mol Biochem Parasitol 1996; 76: 1–10.

    Article  PubMed  CAS  Google Scholar 

  12. Desai SA, Rosenberg RL. Pore size of the malaria parasite’s nutrient channel. Proc Natl Acad Sci USA 1997; 94: 2045–2049.

    Article  PubMed  CAS  Google Scholar 

  13. Waller RF, Keeling PJ, Donald RG, Striepen B, Handman E, Lang-Unnasch N, Cowman AF, Besra GS, Roos DS, McFadden GI. Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proc Natl Acad Sci USA 1998;95:12, 352–12, 357.

    Google Scholar 

  14. Staines HM, Kirk K. Increased choline transport in erythrocytes from mice infected with the malaria parasite Plasmodium vinckei vinckei. Biochem J 1998; 334: 525–530.

    PubMed  CAS  Google Scholar 

  15. Saliba KJ, Homer HA, Kirk K. Transport and metabolism of the essential vitamin pantothetic acid in human erythrocytes infected with the malaria parasite Plasmodium falciparum. J Biol Chem 1998;273:10, 190–10, 195.

    Google Scholar 

  16. Saliba KJ, Kirk K. Uptake of an antiplasmodial protease inhibitor into Plasmodium falciparum-infected human erythrocytes via a parasite-induced pathway. Mol Biochem Parasitol 1998; 94: 297–301.

    Article  PubMed  CAS  Google Scholar 

  17. Schwab JC, Beckers CJ, Joiner KA. The parasitophorous vacuole membrane surrounding intracellular Toxoplasma gondii functions as a molecular sieve. Proc Natl Acad Sci USA 1994; 91: 509–513.

    Article  PubMed  CAS  Google Scholar 

  18. Haldar K. Intracellular trafficking in Plasmodium-infected erythrocytes. Curr Opin Microbiol 1998; 1: 466–471.

    Article  PubMed  CAS  Google Scholar 

  19. Elmendorf HG, Haldar K. Plasmodium falciparum exports the Golgi marker sphingomyelin synthase into a tubovesicular network in the cytoplasm of mature erythrocytes. J Cell Biol 1994; 124: 449–462.

    Article  PubMed  CAS  Google Scholar 

  20. Elmendorf HG, Haldar K. Secretory activities in Plasmodium. Parasitol Today 1993; 9: 98–102.

    Article  PubMed  CAS  Google Scholar 

  21. Elford BC, Ferguson DJP. Secretory Processes in Plasmodium. Parasitol Today 1993; 9: 80–81.

    Article  PubMed  CAS  Google Scholar 

  22. Langreth SG, Jensen JB, Reese RT, Trager W. Fine structure of human malaria in vitro. J Protozool 1978; 443–452.

    Google Scholar 

  23. Matesanz F, Duran-Chica I, Alcina A. The cloning and expression of Pfacsl, a Plasmodium falciparum fatty acyl coenzyme A synthetase-1 targeted to the host erythrocyte cytoplasm. J Mol Biol 1999; 291: 59–70.

    Article  PubMed  CAS  Google Scholar 

  24. Bozdech Z, VanWye J, Haldar K, Schurr E. The human malaria parasite Plasmodium falciparum exports the ATP-binding cassette protein PFGCN20 to membrane structures in the host red blood cell. Mol Biochem Parasitol 1998; 100: 217–222.

    Google Scholar 

  25. Freeman MW. Effluxed lipids: Tangier Island’s latest report. Proc Natl Acad Sci USA 1999;96:10, 950–10, 952.

    Google Scholar 

  26. Pouvelle B, et al. Direct access to serum macromolecules by intraerythrocytic malaria parasites. Nature 1991; 353: 73–75.

    Article  PubMed  CAS  Google Scholar 

  27. Hibbs AR, Stenzel DJ, Saul A. Macromolecular transport in malaria-does the duct exist? Eur J Cell Biol 1997; 72: 182–188.

    PubMed  CAS  Google Scholar 

  28. Haldar K. Ducts channels and transporters in Plasmodium-infected erythrocytes. Parasitol Today 1994; 10: 393–395.

    Article  PubMed  CAS  Google Scholar 

  29. Rathod PK, Khatri A. Synthesis and antiproliferative activity of threo-5-fluoro-Ldihydroorotate. J Biol Chem 1990;265:14, 242–14, 249.

    Google Scholar 

  30. Rathod PK, Khosla M, Gassis S, Young RD, Lutz C. Selection and characterization of 5-fluoroorotate-resistant Plasmodium falciparum. Antimicrob Agents Chemother 1994; 38: 2871–2876.

    Article  PubMed  CAS  Google Scholar 

  31. Jiang JB, Li GQ, Guo XB, Kong YC, Arnold K. Antimalarial activity of mefloquine and qinghaosu. Lancet 1982; 2: 285–288.

    Article  PubMed  CAS  Google Scholar 

  32. Gu HM, Warhurst DC, Peters W. Uptake of [3H]dihydroartemisinine by erythrocytes infected with Plasmodium falciparum in vitro. Trans Soc R Trop Med Hyg 1984; 78: 265–270.

    Article  CAS  Google Scholar 

  33. Gormley JA, Howard RI, Taraschi TF. Trafficking of malarial proteins to the host cell cytoplasm and erythrocyte surface membrane involves multiple pathways. J Cell Biol 1992; 119: 1481–1495.

    Article  PubMed  CAS  Google Scholar 

  34. Lingelbach K. Protein trafficking in the Plasmodium falciparum-infected erythrocyte-from models to mechanisms. Annal Trop Med Parasitol 1997; 91: 543–549.

    Article  CAS  Google Scholar 

  35. Fernandez V, Hommel M, Chen Q, Hagblom P, Wahlgren M. Small, clonally variant antigens expressed on the surface of the Plasmodium falciparum-infected erythrocyte are encoded by the rif gene family and are the target of human immune responses. J Exp Med 1999; 190: 1393–1404.

    Article  PubMed  CAS  Google Scholar 

  36. Kyes SA, Rowe JA, Kriek N, Newbold CI. Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Proc Natl Acad Sci USA 1999; 96: 9333–9338.

    Article  PubMed  CAS  Google Scholar 

  37. Smith JD, Chitnis CE, Craig AG, Roberts DJ, Hudson-Taylor DE, Peterson DS, Piches R, Newbold CI, Miller LH. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 1995; 82: 101–110.

    Article  PubMed  CAS  Google Scholar 

  38. Su X-Z, Heatwole VM, Wertheimer SP, Buinet F, Herrfeldt JA, Peterson DS, Ravetch JA, Wellems TE. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 1995; 82: 89–100.

    Article  PubMed  CAS  Google Scholar 

  39. Baruch DI, Pasloske BL, Singh HB, Bi X, Ma XC, Feldman M, Taraschi TF, Howard RJ. Cloning of the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 1995; 82: 77–87.

    Article  PubMed  CAS  Google Scholar 

  40. Reeder JC, Cowman AF, Davern KM, Beeson JG, Thompson JK, Rogerson SJ, Brown GV. The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1. Proc Natl Acad Sci USA 1999; 96: 5198–5202.

    Article  PubMed  CAS  Google Scholar 

  41. Buffet PA, Gamain B, Scheidig C, Batuch D, Smith JD, Hernandez-Rivas R, Pouvelle B, Oishi S, Fuji N, Fusai T, Parzy D, Miller LH, Gysin J, Scherf A. Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: A receptor for human placental infection. Proc Natl Acad Sci USA 1999;96:12, 743–12, 748.

    Google Scholar 

  42. Rowe JA, Moulds JM, Newbold CI, Miller LH. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor. Nature 1997; 388: 292–295.

    Article  PubMed  CAS  Google Scholar 

  43. B. Sim KL, Chitnis CE, Wasniowska K, Hadley TJ, Miller LH. Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 1994; 264: 1941–1944.

    Article  PubMed  CAS  Google Scholar 

  44. Chitnis CE, Miller LH. Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion. J Exp Med 1994; 180: 497–506.

    Article  PubMed  CAS  Google Scholar 

  45. Kappe SHI, Curley GP, Noe AR, Dalton JP, Adams JH. Erythrocyte binding protein homologues of rodent malaria parasites. Mol Biochem Parasitol 1997; 89: 137–148.

    Article  PubMed  CAS  Google Scholar 

  46. Crabb BS, et al. Targeted gene disruption shows that knobs enable malaria-infected red cells to cytoadhere under physiological shear stress. Cell 1997; 89: 287–296.

    Article  PubMed  CAS  Google Scholar 

  47. Günther K, et al. An exported protein of Plasmodium falciparum is synthesized as an integral membrane protein. Mol Biochem Parasitol 1991; 46: 149–158.

    Article  PubMed  Google Scholar 

  48. Ansorge I, Paprotka K, Bhakdi S, Lingelbach K. Permeabilization of the erythrocyte with streptolysin O allows access to the vacuolar membrane of Plasmodium falciparum and molecular analysis of membrane topology. Mol Biochem Parasitol 1997; 84: 259–261.

    Article  PubMed  CAS  Google Scholar 

  49. Ansorge I, Benting J, Bhakdi S, Lingelbach K. Protein sorting in Plasmodium falciparuminfected red blood cells permeablised with the pore forming protein streptolysin O. Biochem J 1996; 315: 307–314.

    PubMed  CAS  Google Scholar 

  50. Benting J, Mattei D, Lingelbach K. Brefeldin A inhibits transport of glycophorin binding protein from Plasmodium falciparum into the host erythrocyte. Biochem J 1994; 300: 821–826.

    PubMed  CAS  Google Scholar 

  51. Sulli C, Schwartzbach SD. The polyprotein precursor to the Euglena Light-harvesting chlorophyll a/b-binding protein is transported to the Golgi apparatus prior to chloroplast import and polyprotein processing. J Biol Chem 1995;270:13, 084–13, 090.

    Google Scholar 

  52. Warren G. Intracellular membrane morphology. Trans R Soc Lond Series B Biological Studies 1995; 349: 291–295.

    Article  CAS  Google Scholar 

  53. Elmendorf HG, Haldar K. Identification and localization of ERD2 in the malaria parasite Plasmodium falciparum: separation of sites of sphingomyelin synthesis and implications for the organization of the Golgi. EMBO J. 1993; 12: 4763–4773.

    PubMed  CAS  Google Scholar 

  54. Haldar K, Uyetake L, Ghori N, Elmendorf HG, Li W-L. The accumulation and metabolism of a fluorescent ceramide derivative in Plasmodium falciparum-infected erythrocytes. Mol Biochem Parasitol 1991; 49: 143–156.

    Article  PubMed  CAS  Google Scholar 

  55. Alves de Castro F, Ward GE, Jambou R, Attal G, Mayau V, Jaureguiberry G, Braun-Breton C, Chakrabarti D, Langsley G. Identification of a family of Rab G-proteins in Plasmodium falciparum and a detailed characterization of pfrab6. Mol Biochem Parasitol 1996; 80: 77–88.

    Article  Google Scholar 

  56. VanWye J, Ghori N, Webster P, Mitschler RR, Elmendorf HG, Haldar K. Identification and localization of rab6, separation of rab6 from ERD2 and implications for an “unstacked” Golgi in falciparum P. Mol Biochem Parasitol 1996; 83: 107–120.

    Article  CAS  Google Scholar 

  57. Kumar N, Syin C, Carter R, Quakyi I, Miller LH. Plasmodium falciparum gene encoding a protein similar to the 78-kDa rat glucose-regulated stress protein. Proc Natl Acad Sci USA 1988; 85: 6277–6281.

    Article  PubMed  CAS  Google Scholar 

  58. Greca NL, Hibbs AR, Riffkin C, Foley M, Tilley L. Identification of an endoplasmic reticulum-resident calcium-binding protein with multiple EF-hand motifs in asexual stages of Plasmodium falciparuml. Mol Biochem Parasitol 1997; 89: 283–293.

    Article  PubMed  Google Scholar 

  59. Albano FR, Berman A, La Greca N, Hibbs AR, Wickham M, Foley M, Tilley L. A homologue of Sarlp localizes to a novel trafficking pathway in malaria-infected erythrocytes. Eur J Cell Biol 1999; 78: 453–462.

    Article  PubMed  CAS  Google Scholar 

  60. Stafford WH, Stockley RW, B LS, AA H. Isolation A, expression and characterization of the gene for an ADP-ribosylation factor from the human malaria parasite, Plasmodium falciparum. Eur J Biochem 1996; 242: 104–113.

    Article  PubMed  CAS  Google Scholar 

  61. Truong RM, Francis SE, Chakrabarti D, Goldberg DE. Cloning and characterization of Plasmodium falciparum ADP-ribosylation factor and factor-like genes. Mol Biochem Parasitol 1997; 84: 247–253.

    Article  PubMed  CAS  Google Scholar 

  62. Banting G, Benting J, Lingelbach K. A minimalist view of the secretory pathway in Plasmodium falciparum. Trends Cell Biol. 1995; 5: 340–343.

    Article  PubMed  CAS  Google Scholar 

  63. Crary JL, Haldar K. Brefeldin A inhibits protein secretion and parasite maturation in the ring stage of Plasmodium falciparum. Mol Biochem Parasitol 1992; 53: 185–192.

    Article  PubMed  CAS  Google Scholar 

  64. Hinterberg K, Scherf A, Gysin G, Toyoshima T, Aikawa M, Mazie JC, da Silva LP, Mattei D. Plasmodium falciparum: the Pf. 332 antigen is secreted by a brefeldin A dependent pathway and is translocated to the erythrocyte membrane via Maurer’s clefts. Exp Parasitol 1994; 79: 279–291.

    Article  PubMed  CAS  Google Scholar 

  65. Meshnick SR, Thomas A, Ranz A, Xu CM, Pan HZ. Artemisinin (qinghaosu): the role of intrcellualr hemin in its mechanism of antimalarial action. Mol Biochem Parasitol 1991; 49: 181–189.

    Article  PubMed  CAS  Google Scholar 

  66. Hong YL, Yang YZ, Meshnick SR. The interaction of artemisinin with malarial hemozoin. Mol Biochem Parasitol 1994; 63: 121–128.

    Article  PubMed  CAS  Google Scholar 

  67. Beaumelle BD, Vial HJ. Correlation of the efficiency of fatty acid derivatives in suppressing Plasmodium falciparum growth in culture with their inhibitory effect on acyl-CoA synthetase activity. Mol Biochem Parasitol 1998; 28: 39–42.

    Article  Google Scholar 

  68. Roos DS, Crawford MJ, Donald RGK, Fold LM, Hager KM, Kissinger JC, Reynolds MG, Striepen B, Sullivan WJ. Transport and trafficking: Toxoplasma as a model for Plasmodium. Novartis Foundation Symposium, 1998.

    Google Scholar 

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Authors
  1. Kasturi Haldar
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  2. Thomas Akompong
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Editors and Affiliations

  1. School of Medicine, University of California, San Francisco, CA, USA

    Philip J. Rosenthal MD

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Haldar, K., Akompong, T. (2001). Transport and Trafficking in Plasmodium-Infected Red Cells. In: Rosenthal, P.J. (eds) Antimalarial Chemotherapy. Infectious Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-111-4_3

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  • DOI: https://doi.org/10.1007/978-1-59259-111-4_3

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-124-0

  • Online ISBN: 978-1-59259-111-4

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