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The pathogenic basis of malaria

Abstract

Malaria is today a disease of poverty and underdeveloped countries. In Africa, mortality remains high because there is limited access to treatment in the villages. We should follow in Pasteur's footsteps by using basic research to develop better tools for the control and cure of malaria. Insight into the complexity of malaria pathogenesis is vital for understanding the disease and will provide a major step towards controlling it. Those of us who work on pathogenesis must widen our approach and think in terms of new tools such as vaccines to reduce disease. The inability of many countries to fund expensive campaigns and antimalarial treatment requires these tools to be highly effective and affordable.

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Figure 1: The clinical outcome of malarial infection in an African child depends on many parasite, host, geographic and social factors.
Figure 2: Parasite life cycle and pathogenesis of falciparum malaria.
Figure 3: Two families of Plasmodium spp. receptors.
Figure 4: The variant antigen family of PfEMP1 is central to host–parasite interaction and pathogenesis.

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References

  1. Snow, R. W., Craig, M., Deichmann, U. & Marsh, K. Estimating mortality, morbidity and disability due to malaria among Africa's non-pregnant population. Bull. World Health Organ. 77, 624–640 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Marsh, K. et al. Indicators of life-threatening malaria in African children. N. Engl. J. Med. 332, 1399–1404 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Taylor, T. E., Borgstein, A. & Molyneux, M. E. Acid–base status in paediatric Plasmodium falciparum malaria. Q. J. Med. 86, 99–109 (1993).

    CAS  PubMed  Google Scholar 

  4. English, M. et al. Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome. Am. J. Trop. Med. Hyg. 55, 521–524 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. English, M. et al. Acidosis in severe childhood malaria. Q. J. Med. 90, 263–270 (1997).

    Article  CAS  Google Scholar 

  6. Miller, L. H., Shunichi, U. & Chien, S. Alteration in the rheologic properties of Plasmodium knowlesi infected red cells. A possible mechanism of cerebral malaria. J. Clin. Invest. 50, 1451–1455 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dondorp, A. M., Kager, P. A., Vreeken, J. & White, N. J. Abnormal blood flow and red blood cell deformability in severe malaria. Parasitol. Today 16, 228–232 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. English, M. C. et al. Hyponatraemia and dehydration in severe malaria. Arch. Dis. Child. 74, 201–205 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Newton, C. R. et al. Severe anaemia in children living in a malaria endemic area of Kenya. Trop. Med. Int. Health 2, 165–178 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Berkley, J., Mwarumba, S., Bramham, K., Lowe, B. & Marsh, K. Bacteraemia complicating severe malaria in children. Trans. R. Soc. Trop. Med. Hyg. 93, 283–286 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Prada, J., Alabi, S. A. & Bienzle, U. Bacterial strains isolated from blood cultures of Nigerian children with cerebral malaria. Lancet 342, 1114 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. English, M., Waruiru, C. & Marsh, K. Transfusion for respiratory distress in life-threatening childhood malaria. Am. J. Trop. Med. Hyg. 55, 525–530 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Crawley, J. et al. Seizures and status epilepticus in childhood cerebral malaria. Q. J. Med. 89, 591–597 (1996).

    Article  CAS  Google Scholar 

  14. Mendis, K., Sina, B. J., Marchesini, P. & Carter, R. The neglected burden of Plasmodium vivax malaria. Am. J. Trop. Med. Hyg. 64 (Suppl. 1-2), 97–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Mota, M. M. et al. Migration of Plasmodium sporozoites through cells before infection. Science 291, 141–144 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Frevert, U. et al. Malaria circumsporozoite protein binds to heparan sulfate proteoglycans associated with the surface membrane of hepatocytes. J. Exp. Med. 177, 1287–1298 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Chitnis, C. E. Molecular insights into receptors used by malaria parasites for erythrocyte invasion. Curr. Opin. Hematol. 8, 85–91 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Dvorak, J. A., Miller, L. H., Whitehouse, W. C. & Shiroishi, T. Invasion of erythrocytes by malaria merozoites. Science 187, 748–750 (1975).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Aikawa, M., Miller, L. H., Johnson, J. & Rabbege, J. Erythrocyte entry by malarial parasites. A moving junction between erythrocyte and parasite. J. Cell Biol. 77, 72–82 (1978).

    Article  CAS  PubMed  Google Scholar 

  20. Adams, J. H. et al. The Duffy receptor family of Plasmodium knowlesi is located within the micronemes of invasive malaria merozoites. Cell 63, 141–153 (1990).

    Article  CAS  PubMed  Google Scholar 

  21. Kappe, S. et al. Conservation of a gliding motility and cell invasion machinery in Apicomplexan parasites. J. Cell Biol. 147, 937–944 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chotivanich, K. et al. Parasite multiplication potential and the severity of falciparum malaria. J. Infect. Dis. 181, 1206–1209 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Miller, L. H., Mason, S. J., Clyde, D. F. & McGinniss, M. H. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N. Engl. J. Med. 295, 302–304 (1976).

    Article  CAS  PubMed  Google Scholar 

  24. Zimmerman P. A. et al. Emergence of FY*Anull in a Plasmodium vivax-endemic region of Papua New Guinea. Proc. Natl Acad. Sci. USA 96, 13973–13977 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. Adams, J. H. et al. A family of erythrocyte binding proteins of malaria parasites. Proc. Natl Acad. Sci. USA 89, 7085–7089 (1992).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Galinski, M. R., Medina, C. C., Ingravallo, P. & Barnwell, J. W. A reticulocyte-binding protein complex of Plasmodium vivax merozoites. Cell 69, 1213–1226 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Rayner, J. C., Vargas-Serrato, E., Huber, C., Galinski, M. R. & Barnwell, J. W. A Plasmodium falciparum homologue of Plasmodium vivax reticulocyte binding protein (PvRBP1) defines a trypsin-resistant erythocyte invasion pathway. J. Exp. Med. 194, 1571–1582 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Keen, J. K., Sinha, K. A., Brown, K. N. & Holder, A. A. A gene coding for a high-molecular mass rhoptry protein of Plasmodium yoelii. Mol. Biochem. Parasitol. 65, 171–177 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Preiser, P. R., Jarra, W., Capiod, T. & Snounou, G. A rhoptry-protein-associated mechanism of clonal phenotypic variation in rodent malaria. Nature 398, 618–622 (1999).

    Article  ADS  CAS  PubMed  Google Scholar 

  30. Okoyeh, J. N., Pillai, C. R. & Chitnis, C. E. Plasmodium falciparum field isolates commonly use erythrocyte invasion pathways that are independent of sialic acid residues of glycophorin A. Infect. Immun. 67, 5784–5791 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Dolan, S. A., Miller, L. H. & Wellems, T. E. Evidence for a switching mechanism in the invasion of erythrocytes by Plasmodium falciparum. J. Clin. Invest. 86, 618–624 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    Article  ADS  CAS  PubMed  Google Scholar 

  33. Mayer, D. C., Kaneko, O., Hudson-Taylor, D. E., Reid, M. E. & Miller, L. H. Characterization of a Plasmodium falciparum erythrocyte-binding protein paralogous to EBA-175. Proc. Natl Acad. Sci. USA 98, 5222–5227 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. Patel, S. S. et al. The association of the glycophorin C exon 3 deletion with ovalocytosis and malaria susceptibility in the Wosera, Papua New Guinea. Blood 98, 3489–3491 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Patiño, J. A. G., Holder, A. A., McBride, J. S. & Blackman, M. J. Antibodies that inhibit malaria merozoite surface protein-1 processing and erythrocyte invasion are blocked by naturally acquired human antibodies. J. Exp. Med. 186, 1689–1699 (1997).

    Article  Google Scholar 

  36. Hodder, A. N. et al. The disulfide bond structure of Plasmodium apical membrane antigen-1. J. Biol. Chem. 271, 29446–29452 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Triglia, T. et al. Apical membrane antigen 1 plays a central role in erythrocyte invasion by Plasmodium species. Mol. Microbiol. 38, 706–718 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Braun-Breton, C. et al. Plasmodium chabaudi p68 serine protease activity required for merozoite entry into mouse erythrocytes. Proc. Natl Acad. Sci. USA 89,9647–9651 (1992).

    Article  ADS  Google Scholar 

  39. Baruch, D. I. Adhesive receptors on malaria-parasitized red cells. Baillieres Best Pract. Res. Clin. Haematol. 12, 747–761 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Chen, Q., Schlichtherle, M. & Wahlgren, M. Molecular aspects of severe malaria. Clin. Microbiol. Rev. 13, 439–450 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Newbold, C. et al. Cytoadherence, pathogenesis and the infected red cell surface in Plasmodium falciparum. Int. J. Parasitol. 29, 927–937 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Luse, S. A. & Miller, L. H. Plasmodium falciparum malaria. Ultrastructure of parasitized erythrocytes in cardiac vessels. Am. J. Trop. Med. Hyg. 20, 655–660 (1971).

    Article  CAS  PubMed  Google Scholar 

  43. Langreth, S. G. & Peterson, E. Pathogenicity, stability, and immunogenicity of a knobless clone of Plasmodium falciparum in Colombian owl monkeys. Infect. Immun. 47, 760–766 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Cooke, B. M. et al. Rolling and stationary cytoadhesion of red blood cells parasitized by Plasmodium falciparum: separate roles for ICAM-1, CD36 and thrombospondin. Br. J. Haematol. 87, 162–170 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Ho, M. & White, N. J. Molecular mechanisms of cytoadherence in malaria. Am. J. Physiol. 276, C1231–C1242 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Rogerson, S. J., Novakovic, S., Cooke, B. M. & Brown, G. V. Plasmodium falciparum-infected erythrocytes adhere to the proteoglycan thrombomodulin in static and flow-based systems. Exp. Parasitol. 86, 8–18 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Yipp, B. G. et al. Synergism of multiple adhesion molecules in mediating cytoadherence of Plasmodium falciparum-infected erythrocytes to microvascular endothelial cells under flow. Blood 96, 2292–2298 (2000).

    CAS  PubMed  Google Scholar 

  48. Beeson, J. G. et al. Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties. J. Infect. Dis. 180, 464–472 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Newbold, C. et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am. J. Trop. Med. Hyg. 57, 389–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Baruch, D. I. et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77–87 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. Smith, J. D., Subramanian, G., Gamain, B., Baruch, D. I. & Miller, L. H. Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family. Mol. Biochem. Parasitol. 110, 293–310 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Smith, J. D., Gamain, B., Baruch, D. I. & Kyes, S. Decoding the language of var genes and Plasmodium falciparum sequestration. Trends Parasitol. 17,538–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Chen, Q. et al. Developmental selection of var gene expression in Plasmodium falciparum. Nature 394, 392–395 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  56. Roberts, D. J. et al. Rapid switching to multiple antigenic and adhesive phenotypes in malaria. Nature 357, 689–692 (1992).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  57. Snow, R. W. & Marsh, K. New insights into the epidemiology of malaria relevant for disease control. Br. Med. Bull. 54, 293–309 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Fried, M. & Duffy, P. E. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta. Science 272, 1502–1504 (1996).

    Article  ADS  CAS  PubMed  Google Scholar 

  59. Buffet, P. A. et al. Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: a receptor for human placental infection. Proc. Natl Acad. Sci. USA 96, 12743–12748 (1999).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gamain, B., Smith, J. D., Miller, L. H. & Baruch, D. I. Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36. Blood 97, 3268–3274 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Ockenhouse, C. F. et al. Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. J. Infect. Dis. 164, 163–169 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Turner, G. D. et al. An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am. J. Pathol. 145, 1057–1069 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Pain, A. et al. A non-sense mutation in CD36 gene is associated with protection from severe malaria. Lancet 357, 1502–1503 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Rowe, J. A., Moulds, J. M., Newbold, C. I. & Miller, L. H. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature 388, 292–295 (1997).

    Article  ADS  CAS  PubMed  Google Scholar 

  65. Heddini, A. et al. Fresh isolates from children with severe Plasmodium falciparum malaria bind to multiple receptors. Infect. Immun. 69,5848–5856 (2001).

    Article  Google Scholar 

  66. Pain, A. et al. Platelet-mediated clumping of Plasmodium falciparum-infected erythrocytes is a common adhesive phenotype and is associated with severe malaria. Proc. Natl Acad. Sci. USA 98, 1805–1810 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fried, M., Nosten, F., Brockman, A., Brabin, B. J. & Duffy, P. E. Maternal antibodies block malaria. Nature 395, 851–852 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  68. 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 

  69. Bull, P. C., Lowe, B. S., Kortok, M. & Marsh, K. Antibody recognition of Plasmodium falciparum erythrocyte surface antigens in Kenya: evidence for rare and prevalent variants. Infect. Immun. 67, 733–739 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bull, P. C. et al. Plasmodium falciparum-infected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age. J. Infect. Dis. 182, 252–259 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Gupta, S., Snow, R. W., Donnelly, C. A., Marsh, K. & Newbold, C. Immunity to non-cerebral severe malaria is acquired after one or two infections. Nature Med. 5, 340–343 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Clark, I. A. & Cowden, W. B. Why is the pathology of falciparum worse than that of vivax malaria? Parasitol. Today 15, 458–461 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Wong, D. & Dorovini-Zis, K. Upregulation of intercellular adhesion molecule-1 (ICAM-1) expression in primary cultures of human brain microvessel endothelial cells by cytokines and lipopolysaccharide. J. Neuroimmunol. 39, 11–21 (1992).

    Article  CAS  PubMed  Google Scholar 

  74. Levesque, M. C. et al. Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria. J. Infect. Dis. 180, 1994–2002 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Dobbie, M., Crawley, J., Waruiru, C., Marsh, K. & Surtees, R. Cerebrospinal fluid studies in children with cerebral malaria: an excitotoxic mechanism? Am. J. Trop. Med. Hyg. 62, 284–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Schofield, L. & Hackett, F. Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. J. Exp. Med. 177, 145–153 (1993).

    Article  CAS  PubMed  Google Scholar 

  77. Tachado, S. D. et al. Glycosylphosphatidylinositol toxin of Plasmodium induces nitric oxide synthase expression in macrophages and vascular endothelial cells by a protein tyrosine kinase-dependent and protein kinase C-dependent signaling pathway. J. Immunol. 156, 1897–1907 (1996).

    CAS  PubMed  Google Scholar 

  78. Naik, R. S. et al. Glycosylphosphatidylinositol anchors of Plasmodium falciparum: molecular characterization and naturally elicited antibody response that may provide immunity to malaria pathogenesis. J. Exp. Med. 192, 1563–1576 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Toure-Balde, A. et al. Plasmodium falciparum induces apoptosis in human mononuclear cells. Infect. Immun. 64, 744–750 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hirunpetcharat, C. & Good, M. F. Deletion of Plasmodium berghei-specific CD4+ T cells adoptively transferred into recipient mice after challenge with homologous parasite. Proc. Natl Acad. Sci. USA 95, 1715–1720 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. Modiano, D. et al. Different response to Plasmodium falciparum malaria in West African sympatric ethnic groups. Proc. Natl Acad. Sci. USA 93, 13206–13211 (1996).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  82. Modiano, D. et al. Baseline immunity of the population and impact of insecticide-treated curtains on malaria infection. Am. J. Trop. Med. Hyg. 59, 336–340 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank J. Barnwell for help with Fig. 2 and for sharing data before publication.

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Correspondence to Kevin Marsh or Ogobara K. Doumbo.

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Miller, L., Baruch, D., Marsh, K. et al. The pathogenic basis of malaria. Nature 415, 673–679 (2002). https://doi.org/10.1038/415673a

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