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Thromb Haemost 1999; 81(05): 815-821
DOI: 10.1055/s-0037-1614575
Rapid Communication
Schattauer GmbH

Plasmodium Falciparum-infected Erythrocytes: A Mutational Analysis of Cytoadherence via Murine Thrombomodulin

Samia Rabhi-Sabile
1   INSERM U 353, Hôpital Saint-Louis, Paris, France
,
Marta Steiner-Mosonyi
2   From the Departments of Medicine and Medical Biophysics, University of Toronto, Canada
,
Saskia Pollefeyt
3   The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium
,
Desiré Collen
3   The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium
,
B. Pouvelle
4   Unité de Parasitologie Expérimentale and Faculté de Médecine, Université de la Méditerranée, Aix Marseille II, France
,
Jurg Gysin
4   Unité de Parasitologie Expérimentale and Faculté de Médecine, Université de la Méditerranée, Aix Marseille II, France
,
Marie-Claire Boffa
1   INSERM U 353, Hôpital Saint-Louis, Paris, France
,
Edward M. Conway
2   From the Departments of Medicine and Medical Biophysics, University of Toronto, Canada
3   The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium
› Author AffiliationsSupported in part by the Heart and Stroke Foundation of Ontario.
Dr. Conway is a Career Investigator of the Heart and Stroke Foundation of Canada. Dr. Rabhi-Sabile was supported by a Co-operative France-Belgium INSERM-MVG Medical Research Grant.
Further Information

Publication History

Received 17 November 1998

Accepted after revision 22 January 1999

Publication Date:
09 December 2017 (online)

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Summary

The pathophysiologic events leading to organ damage in Plasmo-dium falciparum malaria infections involve adhesion and sequestration of parasite-infected erythrocytes (PRBC) to the vascular endothelium and syncytiotrophoblast. Several potential receptors to which the PRBCs may bind have recently been identified, one of which is thrombomodulin (TM). TM has been implicated particularly in mediating sequestration of P. falciparum-infected erythrocytes in the placenta and brain, two sites of disease associated with high morbidity. In order to establish that binding of parasite-infected red blood cells to TM is dependent on its containing chondroitin-4-sulfate (CSA), we have mutated the CSA-attachment site of murine TM, and expressed this mutant form (TMser-gly) in COS-7 cells. In cytoadhesion assays, we demonstrate that, in contrast to wild-type TM which contains CSA and supports the adhesion of 1466 PRBCs/mm2, TMser-gly does not contain CSA and adhesion of PRBCs to those cells expressing TMser-gly is entirely abrogated (200 PRBCs/mm2). These studies further confirm that the CSA of TM may play a role in the pathophysiology of malaria by providing a binding site for PRBCs.

 

  • References

  • 1 Warrell D, Molyneux M, Beales P. Severe and complicated malaria.. Transactions of the Royal Society of Tropical Medicine and Hygiene 1990; 84: 1
    PubMedGoogle Scholar
  • 2 Fried M, Duffy P. Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta.. Science 1996; 272: 1502
    CrossrefPubMedGoogle Scholar
  • 3 Fried M, Duffy P. Maternal malaria and parasite adhesion.. J Mol Med 1998; 76: 162
    CrossrefPubMedGoogle Scholar
  • 4 Barnwell J, Ockenhouse C, Knowles D. Monoclonal antibody OKM5 inhibits the in vitro binding of Plasmodium falciparum-infected erythrocytes to monocytes, endothelial, and C32 melanoma cells.. J Immunol 1985; 135: 3494
    PubMedGoogle Scholar
  • 5 Roberts D. Thrombospondin binds falciparum malaria parasitized erythrocytes and may mediate cytoadherence.. Nature 1985; 318: 64
    CrossrefPubMedGoogle Scholar
  • 6 Berendt A. Intercellular adhesion molecule-1 is an endothelial cell adhesion molecule for Plasmodium falciparum. . Nature 1989; 341: 57
    CrossrefPubMedGoogle Scholar
  • 7 Ockenhouse C. Human vascular endothelial cell adhesion receptors for Plasmodium falciparum-infected erythrocytes: roles for endothelial leukocyte adhesion molecule 1 and vascular cell adhesion molecule 1.. J Exp Med 1992; 176: 1183
    CrossrefPubMedGoogle Scholar
  • 8 Treutiger C, Heddini H, Fernandez V, Muller W, Wahlgren M. PECAM-1, CD31, and endothelial receptor for binding Plasmodium falciparum-infected erythrocytes.. Nature Medicine 1997; 3: 1405
    CrossrefPubMedGoogle Scholar
  • 9 Robert C, Pouvelle B, Meyer P, Muanza K, Fujioka H, Aikawa M, Scherf A, Gysin J. Chondroitin-4-sulphate (proteoglycan), a receptor for Plasmodium falciparum-infected erythrocyte adherence on brain microvascular endothelial cells.. Res Immunol 1995; 146: 383
    CrossrefPubMedGoogle Scholar
  • 10 Rogerson S, Chaiyaroj S, Ng K, Reeder J, Brown G. Chondroitin sulfate A is a cell surface receptor for Plasmodium falciparum-infected erythrocytes.. J Exp Med 1995; 182: 15
    CrossrefPubMedGoogle Scholar
  • 11 Gysin J, Pouvelle B, Tonqueze M, Edelman L, Boffa M-C.. Chondroitin sulfate of thrombomodulin is an adhesion receptor for Plasmodium falciparum-infected erythrocytes.. Mol Biochem Parasitology 1997; 88:: 267.
    PubMedGoogle Scholar
  • 12 Nawa K, Itani T, Ono M, Sakano K, Marumoto Y, Iwamoto M. The glycosaminoglycan of recombinant human soluble thrombomodulin affectsantithrombotic activity in a rat model of tissue factor-induced disseminated intravascular coagulation.. Thromb Haemost 1992; 67: 366
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Rogerson S, Brown G. Chondroitin sulphate A as an adherence receptor for Plasmodium falciparum-infected erythrocytes.. Parasitology Today 1997; 13: 70
    CrossrefPubMedGoogle Scholar
  • 14 Rogerson S, Novakovic S, Cooke B, Brown G. Plasmodium falciparum-infected erythrocytes adhere to the proteoglycan thrombomodulin in static and flow based systems.. Exp Parasitology 1997; 86: 8
    CrossrefPubMedGoogle Scholar
  • 15 Conway EM, Lau HK, Bauer KA, Rosenberg RD. Development of a radioimmunoassay for quantitating prethrombin 2 in human plasma.. J Lab Clin Med 1987; 110: 567
    PubMedGoogle Scholar
  • 16 Jackman RW, Beeler DL, Fritze L, Soff G, Rosenberg RD. Human thrombomodulin gene is intron depleted: nucleic acid sequences of the cDNA and gene predict protein structure and suggest sites of regulatory control.. Pro Natl Acad Sci (USA) 1987; 84: 6425
    CrossrefPubMedGoogle Scholar
  • 17 Pouvelle B, Fusai T, Gysin J. Revue generale. Plasmodium falciparum et chondroitin-4-sulfate: Le nouveau couple cle de la sequestration.. Med Trop 1998 58. in press
    PubMedGoogle Scholar
  • 18 Gysin J, Hommel M, da Silva P. Experimental infection of the squirrel monkey Saimiri sciureus with Plasmodium falciparum . J Parasitol 1980; 66: 1003
    CrossrefPubMedGoogle Scholar
  • 19 Pouvelle B, Meyer P, Robert C, Bardel L, Gysin J. Chondroitin-4-sulfate impairs in vitro and in vivo cytoadherence of Plasmodium falciparum infected erythrocytes.. Molecular Med 1997; 3: 508
    PubMedGoogle Scholar
  • 20 Gerlitz B, Hassell T, Vlahos CJ, Parkinson JF, Bang NU, Grinnell BW. Identification of the predominant glycosaminoglycan-attachment site in soluble recombinant human thrombomodulin: Potential regulation of functionality by glycosyltransferase competition for serine 474 . Biochem J 1993; 295: 131
    CrossrefPubMedGoogle Scholar
  • 21 Parkinson JF, Grinnell BW, Moore RE, Hoskins J, Vlahos CJ, Bang NU. Stable expression of a secretable deletion mutant of recombinant human thrombomodulin in mammalian cells.. J Biol Chem 1990; 265: 12602
    PubMedGoogle Scholar
  • 22 Aikawa M, Isekin M, Barnwell J, Taylor D, Oo M, Howard R.. The pathology of human cerebral malaria.. Am J Trop Med Hyg (Suppl.) 1990; 43:: 30.
    CrossrefPubMedGoogle Scholar
  • 23 Howard R, Gilladoga A. Molecular studies related to the pathogenesis of cerebral malaria.. Blood 1989; 74: 2603
    PubMedGoogle Scholar
  • 24 Fujioka H, Aikawa M. The molecular basis of pathogenesis of cerebral malaria.. Microb Pathog 1996; 20: 63
    CrossrefPubMedGoogle Scholar
  • 25 Ockenhouse C. The molecular basis for the cytoadherence of Plasmodium falciparum-infected erythrocytes to endothelium.. Cell Biol 1993; 4: 297
    PubMedGoogle Scholar
  • 26 Gay F, Robert C, Pouvelle B, Peyrol S, Scherf A, Gysin J. Isolation and characterization of brain microvascular endothelial cells from Saimiri monkeys. An in vitro model for sequestration of Plasmodium falciparum-infected erythrocytes.. J Immun Methods 1995; 184: 15
    CrossrefPubMedGoogle Scholar
  • 27 Chaiyaroj S, Angkasekwinai P, Buranakiti A, Looareesuwan S, Rogerson S, Brown G. Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: Evidence for chondroitin sulfate A as a cytoadherence receptor.. Am J Trop Med Hyg 1996; 55: 76
    CrossrefPubMedGoogle Scholar
  • 28 Maruyama I, Bell C, Majerus P. Thrombomodulin is found on endothelium of arteries, capillaries, and lymphatics, and on syncytiotrophoblast of human placenta.. J Cell Biol 1985; 101: 363
    CrossrefPubMedGoogle Scholar
  • 29 Boffa M-C, Burke B, Haudenschild C. Preservation of thrombomodulin antigen on vascular and extravascular surfaces.. J Histochem Cytochem 1987; 35: 1267
    CrossrefPubMedGoogle Scholar
  • 30 Pruna A, Peyri N, Berard M, Boffa M-C.. Thrombomodulin is synthesized by human mesangial cells.. Kidney Int 1997; 51:: 687.
    CrossrefPubMedGoogle Scholar
  • 31 Beeson JG, Chai W, Rogerson SJ, Lawson AM, Brown GV. Inhibition of binding of malaria-infected erythrocytes by a tetradecasaccharide fraction from chondroitin sulfate A.. Infect Immun 1998; 66: 3397
    PubMedGoogle Scholar
  • 32 Koyama T, Parkinson JF, Aoki N, Bang NU, Müller BG, Preissner KT. Relationship between post-translational glycosylation and anticoagulant function of secretable recombinant mutants of human thrombomodulin.. Br J Haematol 1991; 78: 515
    CrossrefPubMedGoogle Scholar
  • 33 Saunders S, Jalkanen M, O’Farrel S, Bernfield M. Molecular cloning of syndecan, an integral membrane proteoglycan.. J Cell Biol 1989; 108: 1547
    CrossrefPubMedGoogle Scholar
  • 34 Levine J, Nishiyama A. The Ng2 chondroitin sulfate proteoglycan: a multi-functional proteoglycan associated with immature cells.. Persp Develop Neuro 1996; 3: 245
    PubMedGoogle Scholar
  • 35 Liu W, Litwack E, Stanley M, Langford J, Lander A, Sanderson R. Heparan sulfate proteoglycans as adhesive and anti-invasive molecules. Syn-decans and glypican have distinct functions.. J Biol Chem 1998; 273: 22825
    CrossrefPubMedGoogle Scholar
  • 36 Mitchell E, Fitz-Gibbon L, O’Connor-McCourt M. Subtypes of betaglycan and of type I and type II transforming growth factor α (TGF-α) receptors with different affinities for TGF-α1 and TGF-α2 are exhibitied by human placental trophoblast cells.. J Cell Physiol 1992; 150: 334
    CrossrefPubMedGoogle Scholar
  • 37 Baruch D, Ma X, Singh H, Bi X, Paloske B, Howard R. Identification of a region of PfEMP1 that mediates adherence of Plasmodium falciparum infected erythrocytes to CD 36: conserved fucntion with variant sequence.. Blood 1997; 90: 766
    PubMedGoogle Scholar
  • 38 Su X, Heatwole V, Wertheimer S, Guinet F, Herrfeldt J, Peterson D, Ravetch J, Wellems T. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes.. Cell 1995; 82: 89
    CrossrefPubMedGoogle Scholar
  • 39 Rowe J, Moulds J, Newbold C, Miller L. P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1.. Nature 1997; 388: 292
    CrossrefPubMedGoogle Scholar