Unraveling the C-reactive Protein Complement-Cascade in Destruction of Red Blood Cells: Potential Pathological Implications in <i>Plasmodium Falciparum</i> Malaria

Abstract

Background: Deficiencies of the complementregulatory proteins on RBC (RBC Mal ) of patients with Plasmodium falciparum were reported. Here, we sought to determine the role of affinity-purified Creactive protein from patients (CRP Mal ), in modulating the complement-regulatory proteins and downstream effect on complement-cascade. Methods: CRP Mal was characterized by analytical ultracentrifuge and electrophoretic analysis. Surface plasmon resonance, Western blotting, co-immuno-precipitation, flowcytometry and ELISA determined the binding of CRP Mal with RBC Mal . Modifications of membranes for RBC Mal -CRP Mal binding were explored by scanning electron microscopy, osmotic and turbulence fragility, hydrophobicity and oxyhemoglobin release. Flowcytometry, ELISA, Western blotting and Scatchard analysis monitored the status of complementregulatory proteins on RBC Mal . Complement-activation via CRP Mal was quantified by C3-deposition and hemolysis. Results: CRP Mal binds specifically to RBC Mal through distinct molecules. Such binding altered the normal discoid-shape of RBC Mal with increased membrane fluidity and hydrophobicity. In the presence of CRP, RBC Mal showed reduced complementregulatory 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 CRP Mal causing decreased complement-regulatory proteins, possibly providing a new mechanism of complement-fueled RBC Mal destruction refractory to erythrophagocytosis and may account for pathogenesis of anemia.

Pretreatment elevated erythrocyte sedimentation rate and C-reactive protein as a predictor of malarial complications

“…CRP is found in trace amounts in normal human serum and is markedly increased in inflammatory conditions. CRP activates the complement cascade and could be an important contributor to the accelerated destruction of RBCs in malaria [23]. Thus, CRP, in addition to being an acute-phase marker for complication, could be an active participant in the pathogenesis of this event, which explains the observation of this study that a rise in CRP precedes the development of complications of malaria.…”

Sialylation of Outer Membrane Porin Protein D: A Mechanistic Basis of Antibiotic Uptake in Pseudomonas aeruginosa

“…Non-covalently bound OprD proteins were removed by two fluxes of HCl (20 mM) for 2 min. ␤-lactam antibiotics (10 -100 M) such as piperacillin and ceftazidime (Sigma) were injected separately onto OprD ϩSias or OprD ϪSias coated CM5-sensor chip at a flow rate of 10 l/min (42,43). Bio-Evaluation 3.0 software (Biacore) was used to analyze sensorgrams.…”

The immunological balance between host and parasite in malaria

“…iRBCs are relatively resistant towards complementdependent lysis by the presence of complement regulatory proteins on the plasma membrane of human iRBCs [e.g. CR1, decay accelerating factor (DAF or CD55) and protectin (or membrane inhibitor of reactive lysis (MIRL) or CD59)] (Ansar et al 2009;Ram, Lewis and Rice 2010). This can be circumvented by binding of C-reactive protein (CRP), an acute-phase protein that is increased in plasma of malaria-infected patients, to the red cell membrane (Kremsner et al 1996;Hollestelle et al 2006;Ansar et al 2009;O'Donnell et al 2009).…”

“…CR1, decay accelerating factor (DAF or CD55) and protectin (or membrane inhibitor of reactive lysis (MIRL) or CD59)] (Ansar et al 2009;Ram, Lewis and Rice 2010). This can be circumvented by binding of C-reactive protein (CRP), an acute-phase protein that is increased in plasma of malaria-infected patients, to the red cell membrane (Kremsner et al 1996;Hollestelle et al 2006;Ansar et al 2009;O'Donnell et al 2009). CRP binds to the surface of apoptotic cells, and phosphatidylserine (PS) exposure, a characteristic feature of apoptotic cells, has been observed on the outer surface of iRBCs (Eda and Sherman 2002;Koka et al 2008;Totino et al 2010).…”

“…CRP binds to the surface of apoptotic cells, and phosphatidylserine (PS) exposure, a characteristic feature of apoptotic cells, has been observed on the outer surface of iRBCs (Eda and Sherman 2002;Koka et al 2008;Totino et al 2010). The interaction between CRP and RBCs decreases the expression and the affinity of complement-regulatory proteins and favors complement deposition (Ansar et al 2009). Anti-parasite immunity.…”