Interplay between lipoproteins and bee venom phospholipase A2 in relation to their anti-Plasmodium toxicity.
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.
Guillaume
Carole
C
USM 0504, Biologie Fonctionnelle des Protozoaires, Muséum National d'Histoire Naturelle, Paris, France.
Calzada
Catherine
C
Lagarde
Michel
M
Schrével
Joseph
J
Deregnaucourt
Christiane
C
D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology*; D002417:Cattle; D002914:Chylomicrons / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000469:parasitology; D010741:Phospholipases A / Q000494:pharmacology*; D054467:Phospholipases A2; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001514:Bee Venoms; D002914:Chylomicrons; D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D008244:Lysophosphatidylcholines; D014280:Triglycerides; D012710:Serum Albumin, Bovine; D010741:Phospholipases A; D054467:Phospholipases A2