Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Malaria parasite proteins that remodel the host erythrocyte

Key Points

  • Plasmodium falciparum is responsible for the most virulent form of human malaria. This protozoan parasite spends part of its lifecycle inside the red blood cells (RBCs) of its host. The mature human RBC is a highly differentiated cell (with no internal organelles) that can survive the rigours of the circulatory system. Its membrane shows remarkable deformability and durability, properties that derive from a two-dimensional meshwork of skeletal proteins at the cytoplasmic surface of the cell.

  • The intraerythrocytic malaria parasite induces substantial changes in the morphology, physiology and function of the host cell in ways that are designed to promote parasite survival. The changes are initiated by the export of up to 8% of the parasite's gene products to sites in the RBC cytoplasm and at the RBC membrane. These exported proteins interact with the proteins of the RBC membrane and subvert their normal functions.

  • Immediately after invasion, proteins such as the ring-infected erythrocyte surface antigen (RESA) are exported and interact with spectrin, possibly stabilizing the RBC membrane against the febrile shock that occurs in patients following rupture and re-invasion of infected RBCs.

  • In the early stages of intraerythrocytic growth the parasite exports components that initiate the formation of novel membrane-bound organelles (the tubulovesicular network and Maurer's clefts) that are needed for the export of parasite-derived integral membrane protein cargo.

  • In mature-stage parasites, deposition of a number of parasite proteins at the RBC membrane skeleton compromises the deformability of the host cell membrane. This would lead to removal of infected RBCs by the spleen macrophages; however, the parasite escapes passage through the splenic interendothelial slits by altering the RBC surface to render the cell cytoadhesive.

  • A major feature of mature-stage-infected RBCs is the appearance of knob-like protrusions on the RBCs surface. These knobs interact with the membrane skeleton and act as platforms for the presentation of the major cytoadherence protein, PfEMP1, at the RBC surface. Different variants of PfEMP1 mediate adhesion to host receptor molecules in different organs.

  • Cytoadherence of infected RBCs underlies the virulence of P. falciparum. Sequestration in some locations, such as the brain and placenta, can lead to life-threatening complications, probably initiated by an inappropriate host immune response to the sequestered parasites.

  • The functions of individual exported proteins and their interactions with host cell proteins have been studied using genetic ablation and fluorescent protein fusions in transgenic parasites. Studies of P. falciparum-specific gene products as well as of proteins that are conserved across plasmodial species are gradually revealing the roles of the exported proteins of blood-stage malaria parasites. These studies may point to novel antimalarial strategies.

Abstract

Exported proteins of the malaria parasite Plasmodium falciparum interact with proteins of the erythrocyte membrane and induce substantial changes in the morphology, physiology and function of the host cell. These changes underlie the pathology that is responsible for the deaths of 1–2 million children every year due to malaria infections. The advent of molecular transfection technology, including the ability to generate deletion mutants and to introduce fluorescent reporter proteins that track the locations and dynamics of parasite proteins, has increased our understanding of the processes and machinery for export of proteins in P. falciparum-infected erythrocytes and has provided us with insights into the functions of the parasite protein exportome. We review these developments, focusing on parasite proteins that interact with the erythrocyte membrane skeleton or that promote delivery of the major virulence protein, PfEMP1, to the erythrocyte membrane.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Development of Plasmodium falciparum in human red blood cells.
Figure 2: Adhesion of Plasmodium falciparum -infected red blood cells to endothelial cells.
Figure 3: The membrane skeleton in uninfected and Plasmodium falciparum- infected red blood cells.
Figure 4: Putative protein export pathways in parasitized red blood cells.

Similar content being viewed by others

References

  1. Bannister, L. H., Hopkins, J. M., Fowler, R. E., Krishna, S. & Mitchell, G. H. A brief illustrated guide to the ultrastructure of Plasmodium falciparum asexual blood stages. Parasitol. Today 16, 427–433 (2000). Review of ultrastructural changes in infected RBCs.

    Article  CAS  PubMed  Google Scholar 

  2. Garcia, C. R. et al. Plasmodium in the postgenomic era: new insights into the molecular cell biology of malaria parasites. Int. Rev. Cell. Mol. Biol. 266, 85–156 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Miller, L. H., Baruch, D. I., Marsh, K. & Doumbo, O. K. The pathogenic basis of malaria. Nature 415, 673–679 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Kyes, S., Horrocks, P. & Newbold, C. Antigenic variation at the infected red cell surface in malaria. Annu. Rev. Microbiol. 55, 673–707 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Rowe, J. A. & Kyes, S. A. The role of Plasmodium falciparum var genes in malaria in pregnancy. Mol. Microbiol. 53, 1011–1019 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Deitsch, K. W. & Wellems, T. E. Membrane modifications in erythrocytes parasitized by Plasmodium falciparum. Mol. Biochem. Parasitol. 76, 1–10 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Marti, M., Rug, M., Baum, J., Tilley, L. & Cowman, A. F. Signal mediated export of proteins from the malaria parasite to the host erythrocyte. J. Cell Biol. 171, 587–592 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cooke, B. M., Lingelbach, K., Bannister, L. & Tilley, L. Protein trafficking in Plasmodium falciparum-infected red blood cells. Trends Parasitol. 20, 581–589 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Przyborski, J. M., Wickert, H., Krohne, G. & Lanzer, M. Maurer's clefts — a novel secretory organelle? Mol. Biochem. Parasitol. 132, 17–26 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Lanzer, M., Wickert, H., Krohne, G., Vincensini, L. & Braun Breton, C. Maurer's clefts: A novel multi-functional organelle in the cytoplasm of Plasmodium falciparum-infected erythrocytes. Int. J. Parasitol. 36, 23–36 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Wickert, H. & Krohne, G. The complex morphology of Maurer's clefts: from discovery to three-dimensional reconstructions. Trends Parasitol. 23, 502–509 (2007).

    Article  PubMed  Google Scholar 

  12. Langreth, S. G., Jensen, J. B., Reese, R. T. & Trager, W. Fine structure of human malaria in vitro. J. Protozool. 25, 443–452 (1978).

    Article  CAS  PubMed  Google Scholar 

  13. Hanssen, E. et al. Electron tomography of the Maurer's cleft organelles of Plasmodium falciparum-infected erythrocytes reveals novel structural features. Mol. Microbiol. 67, 703–718 (2008). Electron tomography of infected RBCs reveals novel structural features.

    Article  CAS  PubMed  Google Scholar 

  14. An, X. & Mohandas, N. Disorders of red cell membrane. Br. J. Haematol. 141, 367–375 (2008). Recent review of membrane protein organization in normal and abnormal RBCs.

    CAS  PubMed  Google Scholar 

  15. Yu, J., Fischman, D. A. & Steck, T. L. Selective solubilization of proteins and phospholipids from red blood cell membranes by nonionic detergents. J. Supramol. Struct. 1, 233–248 (1973).

    Article  CAS  PubMed  Google Scholar 

  16. Mohandas, N. & Chasis, J. A. Red blood cell deformability, membrane material properties and shape: regulation by transmembrane, skeletal and cytosolic proteins and lipids. Semin. Hematol. 30, 171–192 (1993).

    CAS  PubMed  Google Scholar 

  17. Luna, E. J. & Hitt, A. L. Cytoskeleton–plasma membrane interactions. Science 258, 955–964 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. An, X. et al. Conformational stabilities of the structural repeats of erythroid spectrin and their functional implications. J. Biol. Chem. 281, 10527–10532 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Shotton, D. M., Burke, B. E. & Branton, D. The molecular structure of human erythrocyte spectrin. Biophysical and electron microscopic studies. J. Mol. Biol. 131, 303–329 (1979).

    Article  CAS  PubMed  Google Scholar 

  20. Yan, Y. et al. Crystal structure of the repetitive segments of spectrin. Science 262, 2027–2030 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. Speicher, D. W., Weglarz, L. & DeSilva, T. M. Properties of human red cell spectrin heterodimer (side-to-side) assembly and identification of an essential nucleation site. J. Biol. Chem. 267, 14775–14782 (1992).

    CAS  PubMed  Google Scholar 

  22. Ursitti, J. A., Kotula, L., DeSilva, T. M., Curtis, P. J. & Speicher, D. W. Mapping the human erythrocyte β-spectrin dimer initiation site using recombinant peptides and correlation of its phasing with the α-actinin dimer site. J. Biol. Chem. 271, 6636–6644 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Shen, B. W., Josephs, R. & Steck, T. L. Ultrastructure of the intact skeleton of the human erythrocyte membrane. J. Cell Biol. 102, 997–1006 (1986).

    Article  CAS  PubMed  Google Scholar 

  24. Derick, L. H., Liu, S. C., Chishti, A. H. & Palek, J. Protein immunolocalization in the spread erythrocyte membrane skeleton. Eur. J. Cell Biol. 57, 317–320 (1992).

    CAS  PubMed  Google Scholar 

  25. Johnson, C. P., Tang, H. Y., Carag, C., Speicher, D. W. & Discher, D. E. Forced unfolding of proteins within cells. Science 317, 663–666 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. An, X., Lecomte, M. C., Chasis, J. A., Mohandas, N. & Gratzer, W. Shear-response of the spectrin dimer-tetramer equilibrium in the red blood cell membrane. J. Biol. Chem. 277, 31796–31800 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Discher, D. E. & Carl, P. New insights into red cell network structure, elasticity, and spectrin unfolding — a current review. Cell. Mol. Biol. Lett. 6, 593–606 (2001).

    CAS  PubMed  Google Scholar 

  28. Dhermy, D., Schrevel, J. & Lecomte, M. C. Spectrin-based skeleton in red blood cells and malaria. Curr. Opin. Hematol. 14, 198–202 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Delaunay, J. The molecular basis of hereditary red cell membrane disorders. Blood Rev. 21, 1–20 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Kennedy, S. P., Warren, S. L., Forget, B. G. & Morrow, J. S. Ankyrin binds to the 15th repetitive unit of erythroid and nonerythroid β -spectrin. J. Cell Biol. 115, 267–277 (1991).

    Article  CAS  PubMed  Google Scholar 

  31. Rubtsov, A. M. & Lopina, O. D. Ankyrins. FEBS Lett. 482, 1–5 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Chang, S. H. & Low, P. S. Identification of a critical ankyrin-binding loop on the cytoplasmic domain of erythrocyte membrane band 3 by crystal structure analysis and site-directed mutagenesis. J. Biol. Chem. 278, 6879–6884 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Michaely, P. & Bennett, V. The ANK repeats of erythrocyte ankyrin form two distinct but cooperative binding sites for the erythrocyte anion exchanger. J. Biol. Chem. 270, 22050–22057 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Bennett, V. & Stenbuck, P. J. The membrane attachment protein for spectrin is associated with band 3 in human erythrocyte membranes. Nature 280, 468–473 (1979).

    Article  CAS  PubMed  Google Scholar 

  35. Tilley, L. & Sawyer, W. H. Rotational dynamics of human erythrocyte band 3: monitoring the aggregation state of an integral membrane protein. Comm. Mol. Cell. Biophys. 7, 333–352 (1992).

    Google Scholar 

  36. Che, A., Morrison, I. E., Pan, R. & Cherry, R. J. Restriction by ankyrin of band 3 rotational mobility in human erythrocyte membranes and reconstituted lipid vesicles. Biochemistry 36, 9588–9595 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Su, Y. et al. Associations of protein 4.2 with band 3 and ankyrin. Mol. Cell Biochem. 289, 159–166 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Van Kim, C. L., Colin, Y. & Cartron, J. P. Rh proteins: key structural and functional components of the red cell membrane. Blood Rev. 20, 93–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Chasis, J. A. & Mohandas, N. Red blood cell glycophorins. Blood 80, 1869–1879 (1992).

    CAS  PubMed  Google Scholar 

  40. Marfatia, S. M., Leu, R. A., Branton, D. & Chishti, A. H. Identification of the protein 4.1 binding interface on glycophorin C and p55, a homologue of the Drosophila discs-large tumor suppressor protein. J. Biol. Chem. 270, 715–719 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Khan, A. A. et al. Dematin and adducin provide a novel link between the spectrin cytoskeleton and human erythrocyte membrane by directly interacting with glucose transporter-1. J. Biol. Chem. 283, 14600–14609 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sim, B. K., Chitnis, C. E., Wasniowska, K., Hadley, T. J. & Miller, L. H. Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 264, 1941–1944 (1994). First identification of a ligand used by P. falciparum for invasion of RBCs.

    Article  CAS  PubMed  Google Scholar 

  43. Duraisingh, M. T., Maier, A. G., Triglia, T. & Cowman, A. F. Erythrocyte-binding antigen 175 mediates invasion in Plasmodium falciparum utilizing sialic acid-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 100, 4796–4801 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Maier, A. G. et al. Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nature Med. 9, 87–92 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Cowman, A. F. & Crabb, B. S. Invasion of red blood cells by malaria parasites. Cell 124, 755–766 (2006).

    Google Scholar 

  46. Duraisingh, M. T. et al. Phenotypic variation of Plasmodium falciparum merozoite proteins directs receptor targeting for invasion of human erythrocytes. EMBO J. 22, 1047–1057 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Baum, J., Papenfuss, A. T., Baum, B., Speed, T. P. & Cowman, A. F. Regulation of apicomplexan actin-based motility. Nature Rev. Microbiol. 4, 621–628 (2006).

    Article  CAS  Google Scholar 

  48. Bannister, L. H. & Dluzewski, A. R. The ultrastructure of red cell invasion in malaria infections: a review. Blood Cells 16, 257–297 (1990).

    CAS  PubMed  Google Scholar 

  49. Remarque, E. J., Faber, B. W., Kocken, C. H. & Thomas, A. W. Apical membrane antigen 1: a malaria vaccine candidate in review. Trends Parasitol. 24, 74–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. Kats, L. M., Cooke, B. M., Coppel, R. L. & Black, C. G. Protein trafficking to apical organelles of malaria parasites — building an invasion machine. Traffic 9, 176–186 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Dowse, T. J., Koussis, K., Blackman, M. J. & Soldati-Favre, D. Roles of proteases during invasion and egress by Plasmodium and Toxoplasma. Subcell. Biochem. 47, 121–139 (2008).

    Article  PubMed  Google Scholar 

  52. Singh, S., Plassmeyer, M., Gaur, D. & Miller, L. H. Mononeme: a new secretory organelle in Plasmodium falciparum merozoites identified by localization of rhomboid-1 protease. Proc. Natl Acad. Sci. USA 104, 20043–20048 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mikkelsen, R. B., Kamber, M., Wadwa, K. S., Lin, P. S. & Schmidt-Ullrich, R. The role of lipids in Plasmodium falciparum invasion of erythrocytes: a coordinated biochemical and microscopic analysis. Proc. Natl Acad. Sci. USA 85, 5956–5960 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, X., Chen, H., Oh, S. S. & Chishti, A. H. A Presenilin-like protease associated with Plasmodium falciparum micronemes is involved in erythrocyte invasion. Mol. Biochem. Parasitol. 158, 22–31 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. McPherson, R. A., Donald, D. R., Sawyer, W. H. & Tilley, L. Proteolytic digestion of band 3 at an external site alters the erythrocyte membrane organisation and may facilitate malarial invasion. Mol. Biochem. Parasitol. 62, 233–242 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Roggwiller, E., Betoulle, M. E., Blisnick, T. & Braun Breton, C. A role for erythrocyte band 3 degradation by the parasite gp76 serine protease in the formation of the parasitophorous vacuole during invasion of erythrocytes by Plasmodium falciparum. Mol. Biochem. Parasitol. 82, 13–24 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Dluzewski, A. R., Fryer, P. R., Griffiths, S., Wilson, R. J. & Gratzer, W. B. Red cell membrane protein distribution during malarial invasion. J. Cell Sci. 92, 691–699 (1989).

    PubMed  Google Scholar 

  58. Dluzewski, A. R. et al. Origins of the parasitophorous vacuole membrane of the malaria parasite, Plasmodium falciparum, in human red blood cells. J. Cell Sci. 102, 527–532 (1992).

    PubMed  Google Scholar 

  59. Culvenor, J. G., Day, K. P. & Anders, R. F. Plasmodium falciparum ring-infected erythrocyte surface antigen is released from merozoite dense granules after erythrocyte invasion. Infect. Immun. 59, 1183–1187 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Vincensini, L., Fall, G., Berry, L., Blisnick, T. & Braun Breton, C. The RhopH complex is transferred to the host cell cytoplasm following red blood cell invasion by Plasmodium falciparum. Mol. Biochem. Parasitol. 160, 81–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Haldar, K. & Mohandas, N. Erythrocyte remodeling by malaria parasites. Curr. Opin. Hematol. 14, 203–209 (2007).

    Article  PubMed  Google Scholar 

  62. Duffy, P. E. & Fried, M. Plasmodium falciparum adhesion in the placenta. Curr. Opin. Microbiol. 6, 371–376 (2003). Review of the mechanisms and consequences of P. falciparum adhesion in the placenta.

    Article  CAS  PubMed  Google Scholar 

  63. Safeukui, I. et al. Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen. Blood 112, 2520–2528 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Atkinson, C. T. & Aikawa, M. Ultrastructure of malaria-infected erythrocytes. Blood Cells 16, 351–368 (1990).

    CAS  PubMed  Google Scholar 

  65. Aikawa, M., Uni, Y., Andrutis, A. T. & Howard, R. J. Membrane-associated electron-dense material of the asexual stages of Plasmodium falciparum: evidence for movement from the intracellular parasite to the erythrocyte membrane. Am. J. Trop. Med. Hyg. 35, 30–36 (1986).

    Article  CAS  PubMed  Google Scholar 

  66. Atkinson, C. T. et al. Ultrastructure of the erythrocytic stages of Plasmodium malariae. J. Protozool. 34, 267–274 (1987).

    Article  CAS  PubMed  Google Scholar 

  67. Tilley, L., Sougrat, R., Lithgow, T. & Hanssen, E. The twists and turns of Maurer's cleft trafficking in P. falciparum-infected erythrocytes. Traffic 9, 187–197 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Wickert, H., Gottler, W., Krohne, G. & Lanzer, M. Maurer's cleft organization in the cytoplasm of Plasmodium falciparum-infected erythrocytes: new insights from three-dimensional reconstruction of serial ultrathin sections. Eur. J. Cell Biol. 83, 567–582 (2004).

    Article  PubMed  Google Scholar 

  69. Taraschi, T. F. et al. Generation of an erythrocyte vesicle transport system by Plasmodium falciparum malaria parasites. Blood 102, 3420–3426 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Kriek, N. et al. Characterization of the pathway for transport of the cytoadherence-mediating protein, PfEMP1, to the host cell surface in malaria parasite-infected erythrocytes. Mol. Microbiol. 50, 1215–1227 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Wickham, M. E. et al. Trafficking and assembly of the cytoadherence complex in Plasmodium falciparum-infected human erythrocytes. EMBO J. 20, 5636–5649 (2001). Use of GFP-transfection technology to define the KAHRP trafficking route and binding domains.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Bhattacharjee, S., van Ooij, C., Balu, B., Adams, J. H. & Haldar, K. Maurer's clefts of Plasmodium falciparum are secretory organelles that concentrate virulence protein reporters for delivery to the host erythrocyte. Blood 111, 2418–2426 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Hayashi, M. et al. A homologue of N-ethylmaleimide-sensitive factor in the malaria parasite Plasmodium falciparum is exported and localized in vesicular structures in the cytoplasm of infected erythrocytes in the brefeldin A-sensitive pathway. J. Biol. Chem. 276, 15249–15255 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Albano, F. R. et al. A homologue of Sar1p localises to a novel trafficking pathway in malaria-infected erythrocytes. Eur. J. Cell Biol. 78, 453–462 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Wickert, H., Rohrbach, P., Scherer, S. J., Krohne, G. & Lanzer, M. A putative Sec23 homologue of Plasmodium falciparum is located in Maurer's clefts. Mol. Biochem. Parasitol. 129, 209–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Adisa, A. et al. Re-assessing the locations of components of the classical vesicle-mediated trafficking machinery in transfected Plasmodium falciparum. Int. J. Parasitol. 37, 1127–1141 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Charpian, S. & Przyborski, J. M. Protein transport across the parasitophorous vacuole of Plasmodium falciparum: into the great wide open. Traffic 9, 157–165 (2008).

    CAS  PubMed  Google Scholar 

  78. Marti, M., Good, R. T., Rug, M., Knuepfer, E. & Cowman, A. F. Targeting malaria virulence and remodeling proteins to the host erythrocyte. Science 306, 1930–1933 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Hiller, N. L. et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection. Science 306, 1934–1937 (2004). References 78 and 79 define the motif that is involved in export of proteins across the PV membrane.

    Article  CAS  PubMed  Google Scholar 

  80. Haldar, K., Kamoun, S., Hiller, N. L., Bhattacharje, S. & van Ooij, C. Common infection strategies of pathogenic eukaryotes. Nature Rev. Microbiol. 4, 922–931 (2006).

    Article  CAS  Google Scholar 

  81. Chang, H. H. et al. N-terminal processing of proteins exported by malaria parasites. Mol. Biochem. Parasitol. 160, 107–115 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Boddey, J. A., Moritz, R. L., Simpson, R. J. & Cowman, A. F. Role of the Plasmodium export element in trafficking parasite proteins to the infected erythrocyte. Traffic 10, 285–299 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ansorge, I., Benting, J., Bhakdi, S. & Lingelbach, K. Protein sorting in Plasmodium falciparum-infected red blood cells permeabilized with the pore-forming protein streptolysin O. Biochem. J. 315, 307–314 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sargeant, T. J. et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol. 7, R12 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. van Ooij, C. et al. The malaria secretome: from algorithms to essential function in blood stage infection. PLoS Pathog. 4, e1000084 (2008). Uses the piggyBac transposition system to estimate the success of exportome predictions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Spycher, C. et al. Genesis of and trafficking to the Maurer's clefts of Plasmodium falciparum-infected erythrocytes. Mol. Cell Biol. 26, 4074–4085 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Dixon, M. W. et al. Targeting of the ring exported protein 1 to the Maurer's clefts is mediated by a two-phase process. Traffic 9, 1316–1326 (2008).

    Article  CAS  PubMed  Google Scholar 

  88. Spycher, C. et al. The Maurer's cleft protein MAHRP1 is essential for trafficking of PfEMP1 to the surface of Plasmodium falciparum-infected erythrocytes. Mol. Microbiol. 68, 1300–1314 (2008). Deletion of MAHRP1 alters Maurer's cleft morphology and interferes with PfEMP1 trafficking to the RBC surface.

    Article  CAS  PubMed  Google Scholar 

  89. Pologe, L. G. & Ravetch, J. V. Large deletions result from breakage and healing of P. falciparum chromosomes. Cell 55, 869–874 (1988).

    Article  CAS  PubMed  Google Scholar 

  90. Scherf, A. & Mattei, D. Cloning and characterization of chromosome breakpoints of Plasmodium falciparum: breakage and new telomere formation occurs frequently and randomly in subtelomeric genes. Nucleic Acids Res. 20, 1491–1496 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Biggs, B. A., Kemp, D. J. & Brown, G. V. Subtelomeric chromosome deletions in field isolates of Plasmodium falciparum and their relationship to loss of cytoadherence in vitro. Proc. Natl Acad. Sci. USA 86, 2428–2432 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cappai, R. et al. Expression of the RESA gene in Plasmodium falciparum isolate FCR3 is prevented by a subtelomeric deletion. Mol. Cell Biol. 9, 3584–3587 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pologe, L. G. & Ravetch, J. V. A chromosomal rearrangement in a P. falciparum histidine-rich protein gene is associated with the knobless phenotype. Nature 322, 474–477 (1986).

    Article  CAS  PubMed  Google Scholar 

  94. Day, K. P. et al. Genes necessary for expression of a virulence determinant and for transmission of Plasmodium falciparum are located on a 0.3-megabase region of chromosome 9. Proc. Natl Acad. Sci. USA 90, 8292–8296 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bourke, P. F., Holt, D. C., Sutherland, C. J. & Kemp, D. J. Disruption of a novel open reading frame of Plasmodium falciparum chromosome 9 by subtelomeric and internal deletions can lead to loss or maintenance of cytoadherence. Mol. Biochem. Parasitol. 82, 25–36 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Maier, A. G. et al. Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell 134, 48–61 (2008). Large-scale project generating loss-of-function mutants for the functional analysis of exported proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Crabb, B. S. et al. Transfection of the human malaria parasite Plasmodium falciparum. Methods Mol. Biol. 270, 263–276 (2004).

    CAS  PubMed  Google Scholar 

  98. Aikawa, M. Studies on falciparum malaria with atomic-force and surface-potential microscopes. Ann. Trop. Med. Parasitol. 91, 689–692 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Glenister, F. K., Coppel, R. L., Cowman, A. F., Mohandas, N. & Cooke, B. M. Contribution of parasite proteins to altered mechanical properties of malaria-infected red blood cells. Blood 99, 1060–1063 (2002). Systematic analysis of the effects of chromosomal deletions on rigidity of infected RBCs.

    Article  CAS  PubMed  Google Scholar 

  100. Nash, G. B., O'Brien, E., Gordon-Smith, E. C. & Dormandy, J. A. Abnormalities in the mechanical properties of red blood cells caused by Plasmodium falciparum. Blood 74, 855–861 (1989).

    CAS  PubMed  Google Scholar 

  101. Foley, M. & Tilley, L. Home improvements: malaria and the red cell. Parasitol. Today 11, 436–439 (1995).

    Article  CAS  PubMed  Google Scholar 

  102. Cooke, B. M., Mohandas, N. & Coppel, R. L. The malaria-infected red blood cell: structural and functional changes. Adv. Parasitol. 50, 1–86 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Parker, P. D., Tilley, L. & Klonis, N. Plasmodium falciparum induces reorganization of host membrane proteins during intraerythrocytic growth. Blood 103, 2404–2406 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Tilley, L. et al. Rotational dynamics of the integral membrane protein, band 3, as a probe of the membrane events associated with Plasmodium falciparum infections of human erythrocytes. Biochim. Biophys. Acta 1025, 135–142 (1990).

    Article  CAS  PubMed  Google Scholar 

  105. Safeukui, I. et al. Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open micro-circulation of the human spleen. Blood 112, 2520–2528 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Cowman, A. F. et al. The ring-infected erythrocyte surface antigen (RESA) polypeptide of Plasmodium falciparum contains two separate blocks of tandem repeats encoding antigenic epitopes that are naturally immunogenic in man. Mol. Biol. Med. 2, 207–221 (1984).

    CAS  PubMed  Google Scholar 

  107. Aikawa, M. et al. Pf155/RESA antigen is localized in dense granules of Plasmodium falciparum merozoites. Exp. Parasitol. 71, 326–329 (1990).

    Article  CAS  PubMed  Google Scholar 

  108. Rug, M., Wickham, M. E., Foley, M., Cowman, A. F. & Tilley, L. Correct promoter control is needed for trafficking of the ring-infected erythrocyte surface antigen to the host cytosol in transfected malaria parasites. Infect. Immun. 72, 6095–6105 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Foley, M., Corcoran, L., Tilley, L. & Anders, R. Plasmodium falciparum: mapping the membrane-binding domain in the ring-infected erythrocyte surface antigen. Exp. Parasitol. 79, 340–350 (1994).

    Article  CAS  PubMed  Google Scholar 

  110. Foley, M., Tilley, L., Sawyer, W. H. & Anders, R. F. The ring-infected erythrocyte surface antigen of Plasmodium falciparum associates with spectrin in the erythrocyte membrane. Mol. Biochem. Parasitol. 46, 137–147 (1991).

    Article  CAS  PubMed  Google Scholar 

  111. Ruangjirachuporn, W. et al. Plasmodium falciparum: analysis of the interaction of antigen Pf155/RESA with the erythrocyte membrane. Exp. Parasitol. 73, 62–72 (1991).

    Article  CAS  PubMed  Google Scholar 

  112. Pei, X. et al. The ring-infected erythrocyte surface antigen (RESA) of Plasmodium falciparum stabilizes spectrin tetramers and suppresses further invasion. Blood 110, 1036–1042 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Da Silva, E. et al. The Plasmodium falciparum protein RESA interacts with the erythrocyte cytoskeleton and modifies erythrocyte thermal stability. Mol. Biochem. Parasitol. 66, 59–69 (1994). References 112 and 113 show the role of RESA in spectrin binding and stabilization.

    Article  CAS  PubMed  Google Scholar 

  114. Silva, M. D. et al. A role for the Plasmodium falciparum RESA protein in resistance against heat shock demonstrated using gene disruption. Mol. Microbiol. 56, 990–1003 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Mills, J. P. et al. Effect of plasmodial RESA protein on deformability of human red blood cells harboring Plasmodium falciparum. Proc. Natl Acad. Sci. USA 104, 9213–9217 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Cooke, B. M., Glenister, F. K., Mohandas, N. & Coppel, R. L. Assignment of functional roles to parasite proteins in malaria-infected red blood cells by competitive flow-based adhesion assay. Br. J. Haematol. 117, 203–211 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Gruenberg, J., Allred, D. R. & Sherman, I. W. Scanning electron microscope-analysis of the protrusions (knobs) present on the surface of Plasmodium falciparum-infected erythrocytes. J. Cell Biol. 97, 795–802 (1983).

    Article  CAS  PubMed  Google Scholar 

  118. Taylor, D. W. et al. Localization of Plasmodium falciparum histidine-rich protein 1 in the erythrocyte skeleton under knobs. Mol. Biochem. Parasitol. 25, 165–174 (1987).

    Article  CAS  PubMed  Google Scholar 

  119. Kilejian, A., Rashid, M. A., Aikawa, M., Aji, T. & Yang, Y. F. Selective association of a fragment of the knob protein with spectrin, actin and the red cell membrane. Mol. Biochem. Parasitol. 44, 175–181 (1991).

    Article  CAS  PubMed  Google Scholar 

  120. Oh, S. S. et al. Plasmodium falciparum erythrocyte membrane protein 1 is anchored to the actin-spectrin junction and knob-associated histidine-rich protein in the erythrocyte skeleton. Mol. Biochem. Parasitol. 108, 237–247 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Chishti, A. H., Andrabi, K. I., Derick, L. H., Palek, J. & Liu, S. C. Isolation of skeleton-associated knobs from human red blood cells infected with malaria parasite Plasmodium falciparum. Mol. Biochem. Parasitol. 52, 283–287 (1992).

    Article  CAS  PubMed  Google Scholar 

  122. Crabb, B. et al. Targeted gene disruption shows that knobs enable malaria-infected red cells to cytoadhere under physiological shear stress. Cell 89, 287–296 (1997). First deletion analysis in P. falciparum. Deletion of KAHRP prevents knob formation and modified adhesion of infected RBCs to endothelial cells.

    Article  CAS  PubMed  Google Scholar 

  123. Crandall, I. & Sherman, I. W. Cytoadherence and the Plasmodium falciparum-infected erythrocyte. Methods Cell Biol. 45, 193–210 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Udomsangpetch, R., Aikawa, M., Berzins, K., Wahlgren, M. & Perlmann, P. Cytoadherence of knobless Plasmodium falciparum-infected erythrocytes and its inhibition by a human monoclonal antibody. Nature 338, 763–765 (1989).

    Article  CAS  PubMed  Google Scholar 

  125. Horrocks, P. et al. PfEMP1 expression is reduced on the surface of knobless Plasmodium falciparum infected erythrocytes. J. Cell Sci. 118, 2507–2518 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Pei, X. et al. Structural and functional studies of interaction between Plasmodium falciparum knob-associated histidine-rich protein (KAHRP) and erythrocyte spectrin. J. Biol. Chem. 280, 31166–31171 (2005). Analysis of the interaction between KAHRP and spectrin.

    Article  CAS  PubMed  Google Scholar 

  127. Magowan, C. et al. Plasmodium falciparum histidine-rich protein 1 associates with the band 3 binding domain of ankyrin in the infected red cell membrane. Biochim. Biophys. Acta 1502, 461–470 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Rug, M., Prescott, S. W., Fernandez, K. M., Cooke, B. M. & Cowman, A. F. The role of KAHRP domains in knob formation and cytoadherence of P. falciparum-infected human erythrocytes. Blood 108, 370–378 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Waller, K. L., Cooke, B. M., Nunomura, W., Mohandas, N. & Coppel, R. L. Mapping the binding domains involved in the interaction between the Plasmodium falciparum knob-associated histidine-rich protein (KAHRP) and the cytoadherence ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1). J. Biol. Chem. 274, 23808–23813 (1999).

    Article  CAS  PubMed  Google Scholar 

  130. Hora, R., Bridges, D. J., Craig, A. & Sharma, A. Erythrocytic casein kinase II regulates cytoadherence of Plasmodium falciparum infected red blood cells. J. Biol. Chem. 284, 6260–6269 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Magowan, C. et al. Role of the Plasmodium falciparum mature-parasite-infected erythrocyte surface antigen (MESA/PfEMP-2) in malarial infection of erythrocytes. Blood 86, 3196–3204 (1995).

    CAS  PubMed  Google Scholar 

  132. Kun, J. F., Waller, K. L. & Coppel, R. L. Plasmodium falciparum: structural and functional domains of the mature-parasite-infected erythrocyte surface antigen. Exp. Parasitol. 91, 258–267 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Magowan, C. et al. Plasmodium falciparum: influence of malarial and host erythrocyte skeletal protein interactions on phosphorylation in infected erythrocytes. Exp. Parasitol. 89, 40–49 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. Bennett, B. J., Mohandas, N. & Coppel, R. L. Defining the minimal domain of the Plasmodium falciparum protein MESA involved in the interaction with the red cell membrane skeletal protein 4.1. J. Biol. Chem. 272, 15299–15306 (1997).

    Article  CAS  PubMed  Google Scholar 

  135. Coppel, R. L. Repeat structures in a Plasmodium falciparum protein (MESA) that binds human erythrocyte protein 4.1. Mol. Biochem. Parasitol. 50, 335–347 (1992).

    Article  CAS  PubMed  Google Scholar 

  136. Waller, K. L. et al. Mature parasite-infected erythrocyte surface antigen (MESA) of Plasmodium falciparum binds to the 30-kDa domain of protein 4.1 in malaria-infected red blood cells. Blood 102, 1911–1914 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Black, C. G. et al. In vivo studies support the role of trafficking and cytoskeletal-binding motifs in the interaction of MESA with the membrane skeleton of Plasmodium falciparum-infected red blood cells. Mol. Biochem. Parasitol. 160, 143–147 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Florens, L. et al. A proteomic view of the Plasmodium falciparum life cycle. Nature 419, 520–526 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Scherf, A., Lopez-Rubio, J. J. & Riviere, L. Antigenic variation in Plasmodium falciparum. Annu. Rev. Microbiol. 62, 445–470 (2008). Recent review of PfEMP1 antigenic variation.

    Article  CAS  PubMed  Google Scholar 

  140. Grobusch, M. P. & Kremsner, P. G. Uncomplicated malaria. Curr. Top. Microbiol. Immunol. 295, 83–104 (2005).

    CAS  PubMed  Google Scholar 

  141. Grau, G. E. et al. Significance of cytokine production and adhesion molecules in malarial immunopathology. Immunol. Lett. 25, 189–194 (1990). Review of the molecular basis of cerebral malaria in human infections and animal models.

    Article  CAS  PubMed  Google Scholar 

  142. Higgins, M. K. The structure of a chondroitin sulfate-binding domain important in placental malaria. J. Biol. Chem. 283, 21842–21846 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Klein, M. M. et al. The cysteine-rich interdomain region from the highly variable Plasmodium falciparum erythrocyte membrane protein-1 exhibits a conserved structure. PLoS Pathog. 4, e1000147 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Tolia, N. H., Enemark, E. J., Sim, B. K. & Joshua-Tor, L. Structural basis for the EBA-175 erythrocyte invasion pathway of the malaria parasite Plasmodium falciparum. Cell 122, 183–193 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Singh, S. K., Hora, R., Belrhali, H., Chitnis, C. E. & Sharma, A. Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain. Nature 439, 741–744 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Taraschi, T. F., Trelka, D., Martinez, S., Schneider, T. & O'Donnell, M. E. Vesicle-mediated trafficking of parasite proteins to the host cell cytosol and erythrocyte surface membrane in Plasmodium falciparum infected erythrocytes. Int. J. Parasitol. 31, 1381–1391 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Knuepfer, E., Rug, M., Klonis, N., Tilley, L. & Cowman, A. F. Trafficking of the major virulence factor to the surface of transfected P. falciparum-infected erythrocytes. Blood 105, 4078–4087 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Papakrivos, J., Newbold, C. I. & Lingelbach, K. A potential novel mechanism for the insertion of a membrane protein revealed by a biochemical analysis of the Plasmodium falciparum cytoadherence molecule PfEMP-1. Mol. Microbiol. 55, 1272–1284 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Frankland, S. et al. Delivery of the malaria virulence protein PfEMP1 to the erythrocyte surface requires cholesterol-rich domains. Eukaryot. Cell 5, 849–860 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Blisnick, T. et al. PfSBP1, a Maurer's cleft Plasmodium falciparum protein, is associated with the erythrocyte skeleton. Mol. Biochem. Parasitol. 111, 107–121 (2000).

    Article  CAS  PubMed  Google Scholar 

  151. Blisnick, T., Vincensini, L., Barale, J. C., Namane, A. & Braun Breton, C. LANCL1, an erythrocyte protein recruited to the Maurer's clefts during Plasmodium falciparum development. Mol. Biochem. Parasitol. 141, 39–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Cooke, B. M. et al. A Maurer's cleft-associated protein is essential for expression of the major malaria virulence antigen on the surface of infected red blood cells. J. Cell Biol. 172, 899–908 (2006). First genetic knockdown of PfEMP1 in malaria parasites and first successful complementation of an asexual blood stage gene in P. falciparum.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Maier, A. G. et al. Skeleton-binding protein 1 functions at the parasitophorous vacuole membrane to traffic PfEMP1 to the Plasmodium falciparum-infected erythrocyte surface. Blood 109, 1289–1297 (2007). References 152 and 153 show that deletion of PfSBP1 interferes with the trafficking of PfEMP1 to the RBC surface.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Spycher, C. et al. MAHRP-1, a novel Plasmodium falciparum histidine-rich protein, binds ferriprotoporphyrin IX and localizes to the Maurer's clefts. J. Biol. Chem. 278, 35373–35383 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Hawthorne, P. L. et al. A novel Plasmodium falciparum ring stage protein, REX, is located in Maurer's clefts. Mol. Biochem. Parasitol. 136, 181–189 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Spielmann, T. et al. A cluster of ring stage-specific genes linked to a locus implicated in cytoadherence in Plasmodium falciparum codes for PEXEL-negative and PEXEL-positive proteins exported into the host cell. Mol. Biol. Cell 17, 3613–3624 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hanssen, E. et al. Targeted mutagenesis of the ring-exported protein-1 of Plasmodium falciparum disrupts the architecture of Maurer's cleft organelles. Mol. Microbiol. 69, 938–953 (2008).

    Article  CAS  PubMed  Google Scholar 

  158. Pasloske, B. L. et al. Cloning and characterization of a Plasmodium falciparum gene encoding a novel high-molecular weight host membrane-associated protein, PfEMP3. Mol. Biochem. Parasitol. 59, 59–72 (1993).

    Article  CAS  PubMed  Google Scholar 

  159. Waterkeyn, J. G. et al. Targeted mutagenesis of Plasmodium falciparum erythrocyte membrane protein 3 (PfEMP3) disrupts cytoadherence of malaria-infected red blood cells. EMBO J. 19, 2813–2823 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Waller, K. L. et al. Interactions of Plasmodium falciparum erythrocyte membrane protein 3 with the red blood cell membrane skeleton. Biochim. Biophys. Acta 1768, 2145–2156 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Knuepfer, E., Rug, M., Klonis, N., Tilley, L. & Cowman, A. F. Trafficking determinants for PfEMP3 export and assembly under the Plasmodium falciparum-infected red blood cell membrane. Mol. Microbiol. 58, 1039–1053 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Pei, X., Guo, X., Coppel, R., Mohandas, N. & An, X. Plasmodium falciparum erythrocyte membrane protein 3 (PfEMP3) destabilizes erythrocyte membrane skeleton. J. Biol. Chem. 282, 26754–26758 (2007). Analysis of the interaction between PfEMP3 and the RBC membrane skeleton.

    Article  CAS  PubMed  Google Scholar 

  163. Moll, K. et al. A novel DBL-domain of the P. falciparum 332 molecule possibly involved in erythrocyte adhesion. PLoS ONE 2, e477 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mattei, D. & Scherf, A. The Pf332 gene of Plasmodium falciparum codes for a giant protein that is translocated from the parasite to the membrane of infected erythrocytes. Gene 110, 71–79 (1992).

    Article  CAS  PubMed  Google Scholar 

  165. Glenister, F. K. et al. Functional alteration of red blood cells by a megadalton protein of Plasmodium falciparum. Blood 113, 919–928 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Hodder, A. N. et al. Analysis of structure and function of the giant protein Pf332 in Plasmodium falciparum. Mol. Microbiol. 71, 48–65 (2009).

    Article  CAS  PubMed  Google Scholar 

  167. Kaviratne, M., Khan, S. M., Jarra, W. & Preiser, P. R. Small variant STEVOR antigen is uniquely located within Maurer's clefts in Plasmodium falciparum-infected red blood cells. Eukaryot. Cell 1, 926–935 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Przyborski, J. M. et al. Trafficking of STEVOR to the Maurer's clefts in Plasmodium falciparum-infected erythrocytes. EMBO J. 24, 2306–2317 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Khattab, A. & Klinkert, M. Q. Maurer's clefts-restricted localization, orientation and export of a Plasmodium falciparum RIFIN. Traffic 7, 1654–1665 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Kyes, S. A., Rowe, J. A., Kriek, N. & Newbold, C. I. Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum. Proc. Natl Acad. Sci. USA 96, 9333–9338 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Sam-Yellowe, T. Y. et al. A Plasmodium gene family encoding Maurer's cleft membrane proteins: structural properties and expression profiling. Genome Res. 14, 1052–1059 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Saridaki, T., Sanchez, C. P., Pfahler, J. & Lanzer, M. A conditional export system provides new insights into protein export in Plasmodium falciparum-infected erythrocytes. Cell. Microbiol. 10, 2483–2495 (2008).

    Article  CAS  PubMed  Google Scholar 

  173. Nunes, M. C., Goldring, J. P., Doerig, C. & Scherf, A. A novel protein kinase family in Plasmodium falciparum is differentially transcribed and secreted to various cellular compartments of the host cell. Mol. Microbiol. 63, 391–403 (2007).

    Article  CAS  PubMed  Google Scholar 

  174. Kun, J. F. et al. A putative Plasmodium falciparum exported serine/threonine protein kinase. Mol. Biochem. Parasitol. 85, 41–51 (1997).

    Article  CAS  PubMed  Google Scholar 

  175. Moskes, C. et al. Export of Plasmodium falciparum calcium-dependent protein kinase 1 to the parasitophorous vacuole is dependent on three N-terminal membrane anchor motifs. Mol. Microbiol. 54, 676–691 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Blisnick, T., Vincensini, L., Fall, G. & Braun-Breton, C. Protein phosphatase 1, a Plasmodium falciparum essential enzyme, is exported to the host cell and implicated in the release of infectious merozoites. Cell. Microbiol. 8, 591–601 (2006).

    Article  CAS  PubMed  Google Scholar 

  177. Tellez, M., Matesanz, F. & Alcina, A. The C-terminal domain of the Plasmodium falciparum acyl-CoA synthetases PfACS1 and PfACS3 functions as ligand for ankyrin. Mol. Biochem. Parasitol. 129, 191–198 (2003).

    Article  CAS  PubMed  Google Scholar 

  178. Elmendorf, H. G. & Haldar, K. Plasmodium falciparum exports the Golgi marker sphingomyelin synthase into a tubovesicular network in the cytoplasm of mature erythrocytes. J. Cell Biol. 124, 449–462 (1994).

    Article  CAS  PubMed  Google Scholar 

  179. Tamez, P. A. et al. An erythrocyte vesicle protein exported by the malaria parasite promotes tubovesicular lipid import from the host cell surface. PLoS Pathog. 4, e1000118 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Vincensini, L. et al. Proteomic analysis identifies novel proteins of the Maurer's clefts, a secretory compartment delivering Plasmodium falciparum proteins to the surface of its host cell. Mol. Cell Proteomics 4, 582–593 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Atkinson, C. T. et al. Ultrastructural localization of erythrocyte cytoskeletal and integral membrane proteins in Plasmodium falciparum-infected erythrocytes. Eur. J. Cell Biol. 45, 192–199 (1988).

    CAS  PubMed  Google Scholar 

  182. Cholera, R. et al. Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. Proc. Natl Acad. Sci. USA 105, 991–996 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Fairhurst, R. M. et al. Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature 435, 1117–1121 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Arie, T., Fairhurst, R. M., Brittain, N. J., Wellems, T. E. & Dvorak, J. A. Hemoglobin C modulates the surface topography of Plasmodium falciparum-infected erythrocytes. J. Struct. Biol. 150, 163–169 (2005).

    Article  CAS  PubMed  Google Scholar 

  185. Kannan, R., Labotka, R. & Low, P. S. Isolation and characterization of the hemichrome-stabilized membrane protein aggregates from sickle erythrocytes. Major site of autologous antibody binding. J. Biol. Chem. 263, 13766–13773 (1988).

    CAS  PubMed  Google Scholar 

  186. Cheetham, M. E. & Caplan, A. J. Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chap. 3, 28–36 (1998).

    Article  CAS  Google Scholar 

  187. Walsh, P., Bursac, D., Law, Y. C., Cyr, D. & Lithgow, T. The J-protein family: modulating protein assembly, disassembly and translocation. EMBO Rep. 5, 567–571 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Botha, M., Pesce, E. R. & Blatch, G. L. The Hsp40 proteins of Plasmodium falciparum and other apicomplexa: regulating chaperone power in the parasite and the host. Int. J. Biochem. Cell Biol. 39, 1781–1803 (2007).

    Article  CAS  PubMed  Google Scholar 

  189. Banumathy, G., Singh, V. & Tatu, U. Host chaperones are recruited in membrane-bound complexes by Plasmodium falciparum. J. Biol. Chem. 277, 3902–3912 (2002).

    Article  CAS  PubMed  Google Scholar 

  190. Cappai, R. et al. Cloning and analysis of the RESA-2 gene: a DNA homologue of the ring-infected erythrocyte surface antigen gene of Plasmodium falciparum. Mol. Biochem. Parasitol. 54, 213–222 (1992).

    Article  CAS  PubMed  Google Scholar 

  191. Daily, J. P. et al. In vivo transcriptome of Plasmodium falciparum reveals overexpression of transcripts that encode surface proteins. J. Infect. Dis. 191, 1196–1203 (2005).

    Article  CAS  PubMed  Google Scholar 

  192. Vazeux, G., Le Scanf, C. & Fandeur, T. The RESA-2 gene of Plasmodium falciparum is transcribed in several independent isolates. Infect. Immun. 61, 4469–4472 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Magowan, C., Wollish, W., Anderson, L. & Leech, J. Cytoadherence by Plasmodium falciparum-infected erythrocytes is correlated with the expression of a family of variable proteins on infected erythrocytes. J. Exp. Med. 168, 1307–1320 (1988).

    Article  CAS  PubMed  Google Scholar 

  194. Baruch, D. I., Gormely, J. A., Ma, C., Howard, R. J. & Pasloske, B. L. Plasmodium falciparum erythrocyte membrane protein 1 is a parasitized erythrocyte receptor for adherence to CD36, thrombospondin, and intercellular adhesion molecule 1. Proc. Natl Acad. Sci. USA 93, 3497–3502 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Rogerson, S. J., Chaiyaroj, S. C., Ng, K., Reeder, J. C. & Brown, G. V. Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes. J. Exp. Med. 182, 15–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  196. Bull, P. C. et al. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nature Med. 4, 358–360 (1998).

    Article  CAS  PubMed  Google Scholar 

  197. Baruch, D. I. et al. Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line. Proc. Natl Acad. Sci. USA 99, 3860–3865 (2002). Demonstration of the importance of PfEMP1 in P. falciparum virulence.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Nolte, D., Hundt, E., Langsley, G. & Knapp, B. A Plasmodium falciparum blood stage antigen highly homologous to the glycophorin binding protein GBP. Mol. Biochem. Parasitol. 49, 253–264 (1991).

    Article  CAS  PubMed  Google Scholar 

  199. Petersen, C. et al. The mature erythrocyte surface antigen of Plasmodium falciparum is not required for knobs or cytoadherence. Mol. Biochem. Parasitol. 36, 61–65 (1989).

    Article  CAS  PubMed  Google Scholar 

  200. Sullivan, D. J. Jr, Gluzman, I. Y. & Goldberg, D. E. Plasmodium hemozoin formation mediated by histidine-rich proteins. Science 271, 219–222 (1996).

    Article  CAS  PubMed  Google Scholar 

  201. Papalexis, V. et al. Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification of the by-products of haemoglobin degradation. Mol. Biochem. Parasitol. 115, 77–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  202. Hanssen, E. et al. Targeted mutagenesis of the ring exported protein-1 of Plasmodium falciparum disrupts the architecture of Maurer's cleft organelles. Mol. Microbiol. 69, 938–953 (2008).

    Article  CAS  PubMed  Google Scholar 

  203. Bozdech, Z. et al. Expression profiling of the schizont and trophozoite stages of Plasmodium falciparum with a long-oligonucleotide microarray. Genome Biol. 4, R9 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Le Roch, K. G. et al. Discovery of gene function by expression profiling of the malaria parasite life cycle. Science 301, 1503–1508 (2003).

    Article  CAS  PubMed  Google Scholar 

  205. Tshefu, K. & James, M. A. Relationship of antibodies to soluble Plasmodium falciparum antigen (Pf70) and protection against malaria in a human population living under intense transmission in Kinshasa, Zaire. Trop. Med. Parasitol. 46, 72–76 (1995).

    CAS  PubMed  Google Scholar 

  206. Wu, Y. & Craig, A. Comparative proteomic analysis of metabolically labelled proteins from Plasmodium falciparum isolates with different adhesion properties. Malar. J. 5, 67 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Smith, J. D. et al. Switches in expression of Plasmodium falciparum var genes correlate with changes in antigenic and cytoadherent phenotypes of infected erythrocytes. Cell 82, 101–110 (1995). Demonstration of PfEMP1 switching as a means of altering the cytoadhesion phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Su, X. Z. et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89–100 (1995). Identification of the PfEMP1 gene family.

    Article  CAS  PubMed  Google Scholar 

  209. Spycher, C. et al. MAHRP-1, a novel Plasmodium falciparum histidine-rich protein, binds ferriprotoporphyrin IX and localizes to the Maurer's clefts. J. Biol. Chem. 278, 35373–35383 (2003).

    Article  CAS  PubMed  Google Scholar 

  210. Saridaki, T., Frohlich, K. S., Braun-Breton, C. & Lanzer, M. Export of PfSBP1 to the Plasmodium falciparum Maurer's clefts. Traffic 10, 137–152 (2009).

    Article  CAS  PubMed  Google Scholar 

  211. Niang, M., Yan Yam, X. & Preiser, P. R. The Plasmodium falciparum STEVOR multigene family mediates antigenic variation of the infected erythrocyte. PLoS Pathog. 5, e1000307 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Thompson, J. et al. Plasmodium cysteine repeat modular proteins 1–4: complex proteins with roles throughout the malaria parasite life cycle. Cell. Microbiol. 9, 1466–1480 (2007).

    Article  CAS  PubMed  Google Scholar 

  213. Spielmann, T., Fergusen, D. J. & Beck, H. P. etramps, a new Plasmodium falciparum gene family coding for developmentally regulated and highly charged membrane proteins located at the parasite–host cell interface. Mol. Biol. Cell 14, 1529–1544 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Birago, C. et al. A gene-family encoding small exported proteins is conserved across Plasmodium genus. Mol. Biochem. Parasitol. 126, 209–218 (2003).

    Article  CAS  PubMed  Google Scholar 

  215. Haase, S. et al. Sequence requirements for the export of the Plasmodium falciparum Maurer's clefts protein REX2. Mol. Microbiol. 71, 1003–1017 (2009).

    Article  CAS  PubMed  Google Scholar 

  216. Lavazec, C., Sanyal, S. & Templeton, T. J. Expression switching in the STEVOR and PfMC-2TM superfamilies in Plasmodium falciparum. Mol. Microbiol. 64, 1621–1634 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Ferguson, Oxford University, UK, for providing micrographs. A.G.M. is an Australian Research Council (ARC) Australian Research Fellow, B.M.C. is a National Health and Medical Research Council (NHMRC) Senior Research Fellow and A.F.C. is a Howard Hughes Medical Institute International Research Scholar. This work was supported by the ARC and the NHMRC.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leann Tilley.

Related links

Supplementary information

Glossary

Cerebral malaria

Complication that is observed in a small subset of P. falciparum infections and is associated with changes in mental status and coma. The mortality ratio is between 25–50%. The histopathological feature of this encephalopathy is the sequestration of parasitized red blood cells (RBCs) and uninfected RBCs to cerebral capillaries and venules.

Exportome

Up to 8% of the parasites gene products contain a putative PEXEL/HT motif and are predicted to be exported to sites in the red blood cell (RBC) cytoplasm and at the RBC membrane.

Tubulovesicular network

Membrane-bound extensions and whorls that emanate from the parasitophorous vacuole membrane. These structures are thought to be involved in the trafficking of lipids and other molecules.

Maurer's clefts

Membrane-bound organelles in the host cell cytoplasm of infected red blood cells (RBCs). These flat and roughly disc-shaped structures are connected to the RBC membrane by tubular tethers. The Maurer's clefts are thought to be involved in the transport of cargo between the parasite and the RBC membrane.

Erythrocyte membrane skeleton

A regular hexagonal array of proteins forming a two-dimensional meshwork at the cytoplasmic surface of the red blood cell comprising spectrin tetramers, actin oligomers, protein 4.1R and accessory proteins.

Knob

Distortions on the surface of P. falciparum-infected red blood cells (RBCs) caused by the deposition and self-assembly of the knob-associated His-rich protein (KAHRP) at the cytoplasmic face of the RBC membrane.

Cytoadherence

An important pathological characteristic of P. falciparum infections is the adherence of mature-stage-infected RBCs to host endothelial cells and placental syncytiotrophoblasts.

Placental malaria

Common complication of malaria in pregnancy in areas of stable transmission, and particularly frequent and severe in women who are pregnant for the first time. Associated with a subpopulation of P. falciparum that sequesters massively in the placenta.

Parasitophorous vacuole membrane

Membrane formed initially by invagination of the red blood cell (RBC) membrane during merozoite invasion. The parasitophorous vacuole membrane expands with the developing parasite and separates the parasite from the RBC cytoplasm.

Electron tomography

An electron-microscope-based method for obtaining detailed three-dimensional images of biological samples. Semi-thin sections (300 nm) of cells are used to collect a series of images at different tilt angles. The images are aligned and tomographic 3D reconstructions of the sample are generated computationally using segmentation tools.

Protein export element/ host targeting (PEXEL/HT) motif

Sequence element (RXLXE) located about 35 amino acids downstream from the hydrophobic signal sequence and usually encoded near the start of exon 2 in a two-exon gene. This motif appears to be cleaved and acetylated in the endoplasmic reticulum and then recognized by a specific transporter in the PV membrane.

DnaJ proteins

Accessory proteins that are involved in the regulation of the molecular chaperone, heat shock protein 70. DnaJ proteins are implicated in protein folding, the assembly and disassembly of higher-order protein structures and the translocation of proteins across membranes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maier, A., Cooke, B., Cowman, A. et al. Malaria parasite proteins that remodel the host erythrocyte. Nat Rev Microbiol 7, 341–354 (2009). https://doi.org/10.1038/nrmicro2110

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro2110

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing