title: In vitro anti-Plasmodium falciparum properties of the full set of human secreted phospholipases A2.
abstract: We have previously shown that secreted phospholipases A2 (sPLA2s) from animal venoms inhibit the in vitro development of Plasmodium falciparum, the agent of malaria. In addition, the inflammatory-type human group IIA (hGIIA) sPLA2 circulates at high levels in the serum of malaria patients. However, the role of the different human sPLA2s in host defense against P. falciparum has not been investigated. We show here that 4 out of 10 human sPLA2s, namely, hGX, hGIIF, hGIII, and hGV, exhibit potent in vitro anti-Plasmodium properties with half-maximal inhibitory concentrations (IC50s) of 2.9 ± 2.4, 10.7 ± 2.1, 16.5 ± 9.7, and 94.2 ± 41.9 nM, respectively. Other human sPLA2s, including hGIIA, are inactive. The inhibition is dependent on sPLA2 catalytic activity and primarily due to hydrolysis of plasma lipoproteins from the parasite culture. Accordingly, purified lipoproteins that have been prehydrolyzed by hGX, hGIIF, hGIII, and hGV are more toxic to P. falciparum than native lipoproteins. However, the total enzymatic activities of human sPLA2s on purified lipoproteins or plasma did not reflect their inhibitory activities on P. falciparum. For instance, hGIIF is 9-fold more toxic than hGV but releases a lower quantity of nonesterified fatty acids (NEFAs). Lipidomic analyses of released NEFAs from lipoproteins demonstrate that sPLA2s with anti-Plasmodium properties are those that release polyunsaturated fatty acids (PUFAs), with hGIIF being the most selective enzyme. NEFAs purified from lipoproteins hydrolyzed by hGIIF were more potent at inhibiting P. falciparum than those from hGV, and PUFA-enriched liposomes hydrolyzed by sPLA2s were highly toxic, demonstrating the critical role of PUFAs. The selectivity of sPLA2s toward low- and high-density (LDL and HDL, respectively) lipoproteins and their ability to directly attack parasitized erythrocytes further explain their anti-Plasmodium activity. Together, our findings indicate that 4 human sPLA2s are active against P. falciparum in vitro and pave the way to future investigations on their in vivo contribution in malaria pathophysiology.
authors.affiliation: Muséum National d'Histoire Naturelle, UMR 7245 CNRS/MNHN, MCAM équipe BAMEE, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Guillaume
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS et Université de Nice Sophia Antipolis, UMR 7275, Sophia Antipolis, Valbonne, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Payré
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS et Université de Nice Sophia Antipolis, UMR 7275, Sophia Antipolis, Valbonne, France.
authors.forename: Ikram
authors.initials: I
authors.lastname: Jemel
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS et Université de Nice Sophia Antipolis, UMR 7275, Sophia Antipolis, Valbonne, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Jeammet
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS et Université de Nice Sophia Antipolis, UMR 7275, Sophia Antipolis, Valbonne, France.
authors.forename: Sofiane
authors.initials: S
authors.lastname: Bezzine
authors.affiliation: Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington, USA.
authors.forename: Gajendra S
authors.initials: GS
authors.lastname: Naika
authors.affiliation: Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bollinger
authors.affiliation: Muséum National d'Histoire Naturelle, UMR 7245 CNRS/MNHN, MCAM équipe BAMEE, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
authors.affiliation: Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.affiliation: Muséum National d'Histoire Naturelle, UMR 7245 CNRS/MNHN, MCAM équipe BAMEE, Paris, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schrével
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS et Université de Nice Sophia Antipolis, UMR 7275, Sophia Antipolis, Valbonne, France deregnau@mnhn.fr lambeau@ipmc.cnrs.fr.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.affiliation: Muséum National d'Histoire Naturelle, UMR 7245 CNRS/MNHN, MCAM équipe BAMEE, Paris, France deregnau@mnhn.fr lambeau@ipmc.cnrs.fr.
authors.forename: Christiane
authors.initials: C
authors.lastname: Deregnaucourt
mesh_terms: D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D004912:Erythrocytes / Q000469:parasitology; D005230:Fatty Acids, Nonesterified; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; D054467:Phospholipases A2
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