Abstract

We previously showed that the in vitro intraerythrocytic development of the malarial agent Plasmodium falciparum is strongly inhibited by secreted phospholipases A(2) (sPLA(2)s) from animal venoms. Inhibition is dependent on enzymatic activity and requires the presence of serum lipoproteins in the parasite culture medium. To evaluate the potential involvement of host lipoproteins and sPLA(2)s in malaria, we investigated the interactions between bee venom phospholipase A(2) (bvPLA(2)), human triglyceride-rich lipoproteins, and infected erythrocytes. Even at high enzyme concentration (100x IC(50)), bvPLA(2) binding to Plasmodium-infected or normal erythrocytes was not detected. On the contrary, tight association with lipoproteins was observed through the formation of buoyant bvPLA(2)/lipoprotein complexes. Direct involvement of the hydrolysis lipid products in toxicity was demonstrated. Arachidonic acid (C20:4), linoleic acid (C18:2), and, to a lesser extent, docosahexaenoic acid (C22:6) appeared as the main actors in toxicity. Minimal oxidation of lipoproteins enhanced toxicity of the lipolyzed particles and induced their interaction with infected or normal erythrocytes. Fresh or oxidized lipolyzed lipoproteins induced the parasite degeneration without host cell membrane disruption, ruling out a possible membranolytic action of fatty acids or peroxidation products in the death process. In conclusion, our data enlighten on the capability of secreted PLA(2)s to exert cytotoxicity via the extracellular generation of toxic lipids, and raise the question of whether such mechanisms could be at play in pathophysiological situations such as malaria.

Highlights

  • We previously showed that the in vitro intraerythrocytic development of the malarial agent Plasmodium falciparum is strongly inhibited by secreted phospholipases A2 from animal venoms

  • We can infer that bee venom phospholipase A2 (bvPLA2) displacement from the coated BSA observed previously in the presence of lipoproteins resulted from a higher enzyme affinity for the lipoproteins than for the BSA, rather than from a competition between the enzyme and the chyl/VLDLs for binding to BSA. These results indicate that the bvPLA2 associates more readily with lipoproteins than with erythrocytes, and strongly suggest that the indirect toxicity of the enzyme toward infected erythrocytes is mainly dictated by its distribution in favor of lipoproteins

  • We show that incubation of oxidized chyls with normal or parasitized erythrocytes leads to a rapid clearance of the apolipoprotein B (apoB)-48 from the supernatant, and that clearance is faster after the Ox-chyl/VLDLs have been lipolyzed by bvPLA2

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Summary

Introduction

We previously showed that the in vitro intraerythrocytic development of the malarial agent Plasmodium falciparum is strongly inhibited by secreted phospholipases A2 (sPLA2s) from animal venoms. To evaluate the potential involvement of host lipoproteins and sPLA2s in malaria, we investigated the interactions between bee venom phospholipase A2 (bvPLA2), human triglyceride-rich lipoproteins, and infected erythrocytes. Interplay between lipoproteins and bee venom phospholipase A2 in relation to their anti-plasmodium toxicity. Phospholipases A2 enzymes (EC 3.1.1.4) exhibit a variety of physiological activities in addition to intrinsic lipolytic action. Those enzymes catalyze the hydrolysis of the sn-2 ester bond of glycerophospholipids, leading to the production of NEFAs and lysophospholipids (lysoPLs).

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