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Infect Immun. 2015 Jun;83(6):2453-65. doi: 10.1128/IAI.02474-14. Epub 2015 Mar 30.

In vitro anti-Plasmodium falciparum properties of the full set of human secreted phospholipases A2.

Author information

1
Muséum National d'Histoire Naturelle, UMR 7245 CNRS/MNHN, MCAM équipe BAMEE, Paris, France.
2
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS et Université de Nice Sophia Antipolis, UMR 7275, Sophia Antipolis, Valbonne, France.
3
Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington, USA.
4
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.
5
Muséum National d'Histoire Naturelle, UMR 7245 CNRS/MNHN, MCAM équipe BAMEE, Paris, France deregnau@mnhn.fr lambeau@ipmc.cnrs.fr.

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.

PMID:
25824843
PMCID:
PMC4432757
DOI:
10.1128/IAI.02474-14
[Indexed for MEDLINE]
Free PMC Article

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