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Background: Deficiencies of the complement-regulatory proteins on RBC (RBCMal) of patients with Plasmodium falciparum were reported. Here, we sought to determine the role of affinity-purified C-reactive protein from patients (CRPMal), in modulating the complement-regulatory proteins and downstream effect on complement-cascade. Methods: CRPMal was characterized by analytical ultracentrifuge and electrophoretic analysis. Surface plasmon resonance, Western blotting, co-immuno-precipitation, flow-cytometry and ELISA determined the binding of CRPMal with RBCMal. Modifications of membranes for RBCMal-CRPMal binding were explored by scanning electron microscopy, osmotic and turbulence fragility, hydrophobicity and oxyhemoglobin release. Flow-cytometry, ELISA, Western blotting and Scatchard analysis monitored the status of complement-regulatory proteins on RBCMal. Complement-activation via CRPMal was quantified by C3-deposition and hemolysis. Results: CRPMal binds specifically to RBCMal through distinct molecules. Such binding altered the normal discoid-shape of RBCMal with increased membrane fluidity and hydrophobicity. In the presence of CRP, RBCMal showed reduced complement-regulatory proteins (CR1 or CD35, CD55 and CD59) with decreased affinity. These changes caused enhanced C3-deposition and complement-mediated hemolysis. Conclusion: Taken together, we have established the contributory effect of CRPMal causing decreased complement-regulatory proteins, possibly providing a new mechanism of complement-fueled RBCMal destruction refractory to erythrophagocytosis and may account for pathogenesis of anemia. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]