Cytoadherence of Plasmodium falciparum-infected erythrocytes is mediated by a redox-dependent conformational fraction of CD36.
The adherence of Plasmodium falciparum-infected RBC (IRBC) to postcapillary venular endothelium is an important determinant of the pathogenesis of severe malaria complications. Cytoadherence of IRBC to endothelial cells involves specific receptor/ligand interactions. The glycoprotein CD36 expressed on endothelial cells is the major receptor involved in this interaction. Treatment of CD36-expressing cells with reducing agents, such as DTT and N-acetylcysteine, was followed by CD36 conformational change monitorable by the appearance of the Mo91 mAb epitope. Only a fraction of the surface expressed CD36 molecules became Mo91 positive, suggesting the presence of two subpopulations of molecules with different sensitivities to reduction. The Mo91 epitope has been localized on a peptide (residues 260-279) of the C-terminal, cysteine-rich region of CD36. Treatment with reducing agents inhibited the CD36-dependent cytoadherence of IRBC to CD36-expressing cells and dissolved pre-existent CD36-mediated IRBC/CD36-expressing cell aggregates. CD36 reduction did not impair the functionality of CD36, since the reactivity of other anti-CD36 mAbs as well as the binding of oxidized low density lipoprotein, a CD36 ligand, were maintained. The modifications induced by reduction were reversible. After 14 h CD36 was reoxidized, the cells did not express the Mo91 epitope, and cytoadherence to IRBC was restored. The results indicate that IRBCs bind only to a redox-modulated fraction of CD36 molecules expressed on the cell surface. The present data indicate the therapeutic potential of reducing agents, such as the nontoxic drug N-acetylcysteine, to prevent or treat malaria complications due to IRBC cytoadhesion.
Gruarin
P
P
DIBIT, San Raffaele Scientific Institute, Milan, Italy.
Primo
L
L
Ferrandi
C
C
Bussolino
F
F
Tandon
N N
NN
Arese
P
P
Ulliers
D
D
Alessio
M
M
D000111:Acetylcysteine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000937:Antigen-Antibody Reactions; D018955:CD36 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D019556:COS Cells; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D005591:Chemical Fractionation; D003545:Cysteine / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D004903:Erythrocyte Aggregation / Q000187:drug effects / Q000276:immunology; D004912:Erythrocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects / Q000276:immunology*; D011487:Protein Conformation / Q000187:drug effects; D019163:Reducing Agents / Q000494:pharmacology; D020298:U937 Cells
D000911:Antibodies, Monoclonal; D018955:CD36 Antigens; D000939:Epitopes; D019163:Reducing Agents; D003545:Cysteine; D004229:Dithiothreitol; D000111:Acetylcysteine