Antimalarial Activity of Human Group IIA Secreted Phospholipase A₂in Relation to Enzymatic Hydrolysis of Oxidized Lipoproteins

Abstract

The level of human group IIA secreted phospholipase A2 (hGIIA sPLA2) is increased in the plasma of malaria patients, but its role is unknown. In parasite culture with normal plasma, hGIIA is inactive against Plasmodium falciparum, contrasting with hGIIF, hGV, and hGX sPLA2s, which readily hydrolyze plasma lipoproteins, release nonesterified fatty acids (NEFAs), and inhibit parasite growth. Here, we revisited the anti-Plasmodium activity of hGIIA under conditions closer to those of malaria physiopathology where lipoproteins are oxidized. In parasite culture containing oxidized lipoproteins, hGIIA sPLA2 was inhibitory, with a 50% inhibitory concentration value of 150.0 ± 40.8 nM, in accordance with its capacity to release NEFAs from oxidized particles. With oxidized lipoproteins, hGIIF, hGV, and hGX sPLA2s were also more potent, by 4.6-, 2.1-, and 1.9-fold, respectively. Using specific immunoassays, we found that hGIIA sPLA2 is increased in plasma from 41 patients with malaria over levels for healthy donors (median [interquartile range], 1.6 [0.7 to 3.4] nM versus 0.0 [0.0 to 0.1] nM, respectively; P < 0.0001). Other sPLA2s were not detected. Malaria plasma, but not normal plasma, contains oxidized lipoproteins and was inhibitory to P. falciparum when spiked with hGIIA sPLA2. Injection of recombinant hGIIA into mice infected with P. chabaudi reduced the peak of parasitemia, and this was effective only when the level of plasma peroxidation was increased during infection. In conclusion, we propose that malaria-induced oxidation of lipoproteins converts these into a preferential substrate for hGIIA sPLA2, promoting its parasite-killing effect. This mechanism may contribute to host defense against P. falciparum in malaria where high levels of hGIIA are observed.

Updating Phospholipase A2 Biology

“…Several sPLA 2 s, including sPLA 2 -IIF, -V and -X, which efficiently hydrolyze plasma lipoproteins to release free fatty acids, have the capacity to inhibit parasite growth in vitro, yet these sPLA 2 s are undetectable in human plasma. sPLA 2 -IIA, though hardly hydrolyzing normal lipoproteins, is increased in the plasma of malaria patients and hydrolyzes “oxidized” lipoproteins to block Plasmodium growth [ 26 ]. Injection of recombinant sPLA 2 -IIA into Plasmodium -infected mice reduces the peak of parasitemia when the level of plasma peroxidation is increased during infection.…”

Bee Venom: An Updating Review of Its Bioactive Molecules and Its Health Applications

“…Besides, melittin showed no toxicity in a study in vivo with mice that before treatment with melittin showed resistance to a lethal dose of influenza a virus [71]. At last, it has been also suggested using BV and, particularly, PLA2 as an antiparasitic agent in the treatment against some organisms such as Trypanosoma brucei brucei or Plasmodium falciparum [44,45].…”

Human Group IIA Phospholipase A2—Three Decades on from Its Discovery

“…Recent research by Dacheux et al [ 65 ] highlights that hGIIA’s role in host defense extends beyond anti-bactericidal properties to anti-malarial properties. Other sPLA 2 s human group IIF, hGV and hGX hydrolyze phospholipids present in lipoproteins producing non-esterified fatty acids such as polyunsaturated fatty acids that are highly toxic to the malaria pathogen, Plasmodium falciparum , however these sPLA 2 s are not detected in the plasma of infected patients [ 65 ]. Conversely, hGIIA has low affinity for these lipoproteins, but more effectively hydrolyses their oxidized counterparts, which are present in higher concentrations in plasma from malaria patients [ 65 ].…”

“…Other sPLA 2 s human group IIF, hGV and hGX hydrolyze phospholipids present in lipoproteins producing non-esterified fatty acids such as polyunsaturated fatty acids that are highly toxic to the malaria pathogen, Plasmodium falciparum , however these sPLA 2 s are not detected in the plasma of infected patients [ 65 ]. Conversely, hGIIA has low affinity for these lipoproteins, but more effectively hydrolyses their oxidized counterparts, which are present in higher concentrations in plasma from malaria patients [ 65 ]. hGIIA is up-regulated in the plasma of patients with malaria, catalyzes these oxidized phospholipids present in lipoproteins, promoting its parasite-killing effect [ 65 ].…”