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. 1996 Apr;64(4):1373–1378. doi: 10.1128/iai.64.4.1373-1378.1996

Sulfated polyanions inhibit invasion of erythrocytes by plasmodial merozoites and cytoadherence of endothelial cells to parasitized erythrocytes.

L Xiao 1, C Yang 1, P S Patterson 1, V Udhayakumar 1, A A Lal 1
PMCID: PMC173928  PMID: 8606103

Abstract

Sulfated proteoglycans have been shown to be involved in the binding of sporozoites of malaria parasites to hepatocytes. In this study, we have evaluated the effect of sulfated glycosaminoglycans on the invasion of erythrocytes by Plasmodium falciparum merozoites and cytoadherence of parasitized erythrocytes (PRBC) to endothelial cells. Invasion of erythrocytes by HB3EC-6 (an HB3 line selected for high binding to endothelial cells) was inhibited by dextran sulfate 500K, dextran sulfate 5K, sulfatides, fucoidan, and heparin but not by chondroitin sulfate A. With the exception of sulfatides, the invasion-inhibitory effect was not mediated by killing of parasites. Cytoadherence of HB3EC-6 to human microvascular endothelial cells (HMEC-1) and inhibited by these sulfated glycoconjugates. The highly sulfated dextran sulfate 500K had the highest inhibitory effect on both invasion and cytoadherence, whereas the positively charged protamine sulfate promoted cytoadherence. Because preincubation of PRBC with sulfated glycosaminoglycans and treatment of target cells with heparinase had no significant inhibition on cytoadherence, it is unlikely that sulfated glycoconjugates are used directly by endothelial cells as cytoadhesion receptors. In an vivo experiment, we found that the administration of dextran sulfate 500K to CBA/Ca mice infected with Plasmodium berghei ANKA reduced parasitemia and delayed the death associated with anemia. These observations suggest that sulfated polyanions inhibit the invasion of erythrocytes by merozoites and cytoadherence of PRBC to endothelial cells by increasing negative repulsive charge and sterically interfering with the ligand-receptor interaction after binding to target cells.

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Selected References

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  1. Ades E. W., Candal F. J., Swerlick R. A., George V. G., Summers S., Bosse D. C., Lawley T. J. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol. 1992 Dec;99(6):683–690. doi: 10.1111/1523-1747.ep12613748. [DOI] [PubMed] [Google Scholar]
  2. Butcher G. A., Parish C. R., Cowden W. B. Inhibition of growth in vitro of Plasmodium falciparum by complex polysaccharides. Trans R Soc Trop Med Hyg. 1988;82(4):558–559. doi: 10.1016/0035-9203(88)90504-4. [DOI] [PubMed] [Google Scholar]
  3. Carlson J., Ekre H. P., Helmby H., Gysin J., Greenwood B. M., Wahlgren M. Disruption of Plasmodium falciparum erythrocyte rosettes by standard heparin and heparin devoid of anticoagulant activity. Am J Trop Med Hyg. 1992 May;46(5):595–602. doi: 10.4269/ajtmh.1992.46.595. [DOI] [PubMed] [Google Scholar]
  4. Cavari S., Vannucchi S. Glycosaminoglycans exposed on the endothelial cell surface. Binding of heparin-like molecules derived from serum. FEBS Lett. 1993 May 24;323(1-2):155–158. doi: 10.1016/0014-5793(93)81469-g. [DOI] [PubMed] [Google Scholar]
  5. Cerami C., Frevert U., Sinnis P., Takacs B., Clavijo P., Santos M. J., Nussenzweig V. The basolateral domain of the hepatocyte plasma membrane bears receptors for the circumsporozoite protein of Plasmodium falciparum sporozoites. Cell. 1992 Sep 18;70(6):1021–1033. doi: 10.1016/0092-8674(92)90251-7. [DOI] [PubMed] [Google Scholar]
  6. Chaiyaroj S. C., Coppel R. L., Novakovic S., Brown G. V. Multiple ligands for cytoadherence can be present simultaneously on the surface of Plasmodium falciparum-infected erythrocytes. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10805–10808. doi: 10.1073/pnas.91.23.10805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Curfs J. H., van der Meide P. H., Billiau A., Meuwissen J. H., Eling W. M. Plasmodium berghei: recombinant interferon-gamma and the development of parasitemia and cerebral lesions in malaria-infected mice. Exp Parasitol. 1993 Sep;77(2):212–223. doi: 10.1006/expr.1993.1078. [DOI] [PubMed] [Google Scholar]
  8. Dalton J. P., Hudson D., Adams J. H., Miller L. H. Blocking of the receptor-mediated invasion of erythrocytes by Plasmodium knowlesi malaria with sulfated polysaccharides and glycosaminoglycans. Eur J Biochem. 1991 Feb 14;195(3):789–794. doi: 10.1111/j.1432-1033.1991.tb15767.x. [DOI] [PubMed] [Google Scholar]
  9. Dennis L. H., Conrad M. E. Anticoagulant and antimalarial action of heparin in simian malaria. Lancet. 1968 Apr 13;1(7546):769–771. doi: 10.1016/s0140-6736(68)92225-3. [DOI] [PubMed] [Google Scholar]
  10. Dolan S. A., Proctor J. L., Alling D. W., Okubo Y., Wellems T. E., Miller L. H. Glycophorin B as an EBA-175 independent Plasmodium falciparum receptor of human erythrocytes. Mol Biochem Parasitol. 1994 Mar;64(1):55–63. doi: 10.1016/0166-6851(94)90134-1. [DOI] [PubMed] [Google Scholar]
  11. Frevert U. Malaria sporozoite-hepatocyte interactions. Exp Parasitol. 1994 Sep;79(2):206–210. doi: 10.1006/expr.1994.1082. [DOI] [PubMed] [Google Scholar]
  12. Grau G. E., Piguet P. F., Engers H. D., Louis J. A., Vassalli P., Lambert P. H. L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol. 1986 Oct 1;137(7):2348–2354. [PubMed] [Google Scholar]
  13. Hemmer C. J., Kern P., Holst F. G., Nawroth P. P., Dietrich M. Neither heparin nor acetylsalicylic acid influence the clinical course in human Plasmodium falciparum malaria: a prospective randomized study. Am J Trop Med Hyg. 1991 Nov;45(5):608–612. doi: 10.4269/ajtmh.1991.45.608. [DOI] [PubMed] [Google Scholar]
  14. Jensen J. B. Concentration from continuous culture of erythrocytes infected with trophozoites and schizonts of Plasmodium falciparum. Am J Trop Med Hyg. 1978 Nov;27(6):1274–1276. doi: 10.4269/ajtmh.1978.27.1274. [DOI] [PubMed] [Google Scholar]
  15. Kulane A., Ekre H. P., Perlmann P., Rombo L., Wahlgren M., Wahlin B. Effect of different fractions of heparin on Plasmodium falciparum merozoite invasion of red blood cells in vitro. Am J Trop Med Hyg. 1992 May;46(5):589–594. doi: 10.4269/ajtmh.1992.46.589. [DOI] [PubMed] [Google Scholar]
  16. Lynch G., Low L., Li S., Sloane A., Adams S., Parish C., Kemp B., Cunningham A. L. Sulfated polyanions prevent HIV infection of lymphocytes by disruption of the CD4-gp120 interaction, but do not inhibit monocyte infection. J Leukoc Biol. 1994 Sep;56(3):266–272. doi: 10.1002/jlb.56.3.266. [DOI] [PubMed] [Google Scholar]
  17. Miller L. H., Good M. F., Milon G. Malaria pathogenesis. Science. 1994 Jun 24;264(5167):1878–1883. doi: 10.1126/science.8009217. [DOI] [PubMed] [Google Scholar]
  18. Müller H. M., Reckmann I., Hollingdale M. R., Bujard H., Robson K. J., Crisanti A. Thrombospondin related anonymous protein (TRAP) of Plasmodium falciparum binds specifically to sulfated glycoconjugates and to HepG2 hepatoma cells suggesting a role for this molecule in sporozoite invasion of hepatocytes. EMBO J. 1993 Jul;12(7):2881–2889. doi: 10.1002/j.1460-2075.1993.tb05950.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Noel G. J., Love D. C., Mosser D. M. High-molecular-weight proteins of nontypeable Haemophilus influenzae mediate bacterial adhesion to cellular proteoglycans. Infect Immun. 1994 Sep;62(9):4028–4033. doi: 10.1128/iai.62.9.4028-4033.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ockenhouse C. F., Ho M., Tandon N. N., Van Seventer G. A., Shaw S., White N. J., Jamieson G. A., Chulay J. D., Webster H. K. Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. J Infect Dis. 1991 Jul;164(1):163–169. doi: 10.1093/infdis/164.1.163. [DOI] [PubMed] [Google Scholar]
  21. Ortega-Barria E., Pereira M. E. A novel T. cruzi heparin-binding protein promotes fibroblast adhesion and penetration of engineered bacteria and trypanosomes into mammalian cells. Cell. 1991 Oct 18;67(2):411–421. doi: 10.1016/0092-8674(91)90192-2. [DOI] [PubMed] [Google Scholar]
  22. Pancake S. J., Holt G. D., Mellouk S., Hoffman S. L. Malaria sporozoites and circumsporozoite proteins bind specifically to sulfated glycoconjugates. J Cell Biol. 1992 Jun;117(6):1351–1357. doi: 10.1083/jcb.117.6.1351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pasloske B. L., Howard R. J. Malaria, the red cell, and the endothelium. Annu Rev Med. 1994;45:283–295. doi: 10.1146/annurev.med.45.1.283. [DOI] [PubMed] [Google Scholar]
  24. Reid H. A., Sucharit P. Ancrod, heparin, and -aminocaproic acid in simian Knowlesi malaria. Lancet. 1972 Nov 25;2(7787):1110–1112. doi: 10.1016/s0140-6736(72)92716-x. [DOI] [PubMed] [Google Scholar]
  25. 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. 1995 Jul 1;182(1):15–20. doi: 10.1084/jem.182.1.15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rogerson S. J., Reeder J. C., al-Yaman F., Brown G. V. Sulfated glycoconjugates as disrupters of Plasmodium falciparum erythrocyte rosettes. Am J Trop Med Hyg. 1994 Aug;51(2):198–203. doi: 10.4269/ajtmh.1994.51.198. [DOI] [PubMed] [Google Scholar]
  27. Rowe A., Berendt A. R., Marsh K., Newbold C. I. Plasmodium falciparum: a family of sulphated glycoconjugates disrupts erythrocyte rosettes. Exp Parasitol. 1994 Dec;79(4):506–516. doi: 10.1006/expr.1994.1111. [DOI] [PubMed] [Google Scholar]
  28. Seed T. M., Kreier J. P. Surface properties of extracellular malaria parasites: electrophoretic and lectin-binding characteristics. Infect Immun. 1976 Dec;14(6):1339–1347. doi: 10.1128/iai.14.6.1339-1347.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sein K. K., Maeno Y., Thuc H. V., Anh T. K., Aikawa M. Differential sequestration of parasitized erythrocytes in the cerebrum and cerebellum in human cerebral malaria. Am J Trop Med Hyg. 1993 Apr;48(4):504–511. doi: 10.4269/ajtmh.1993.48.504. [DOI] [PubMed] [Google Scholar]
  30. 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. 1994 Jun 24;264(5167):1941–1944. doi: 10.1126/science.8009226. [DOI] [PubMed] [Google Scholar]
  31. Sivaraman C. A., Rai Chowdhuri A. N. Effect of heparin sodium on in vitro development of Plasmodium falciparum. Indian J Exp Biol. 1983 May;21(5):247–250. [PubMed] [Google Scholar]
  32. Trager W., Jensen J. B. Human malaria parasites in continuous culture. Science. 1976 Aug 20;193(4254):673–675. doi: 10.1126/science.781840. [DOI] [PubMed] [Google Scholar]
  33. Van Damme M. P., Tiglias J., Nemat N., Preston B. N. Determination of the charge content at the surface of cells using a colloid titration technique. Anal Biochem. 1994 Nov 15;223(1):62–70. doi: 10.1006/abio.1994.1547. [DOI] [PubMed] [Google Scholar]
  34. WuDunn D., Spear P. G. Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol. 1989 Jan;63(1):52–58. doi: 10.1128/jvi.63.1.52-58.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zhang Q., Young T. F., Ross R. F. Microtiter plate adherence assay and receptor analogs for Mycoplasma hyopneumoniae. Infect Immun. 1994 May;62(5):1616–1622. doi: 10.1128/iai.62.5.1616-1622.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]

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