Abstract
We previously showed that injection of recombinant human group IIA secreted phospholipase A2 (hGIIA sPLA2) to Plasmodium chabaudi-infected mice lowers parasitaemia by 20%. Here, we show that transgenic (TG) mice overexpressing hGIIA sPLA2 have a peak of parasitaemia about 30% lower than WT littermates. During infection, levels of circulating sPLA2, enzymatic activity and plasma lipid peroxidation were maximal at day-14, the peak of parasitaemia. Levels of hGIIA mRNA increased in liver but not in spleen and blood cells, suggesting that liver may contribute as a source of circulating hGIIA sPLA2. Before infection, baseline levels of leukocytes and pro-inflammatory cytokines were higher in TG mice than WT littermates. Upon infection, the number of neutrophils, lymphocytes and monocytes increased and were maximal at the peak of parasitaemia in both WT and TG mice, but were higher in TG mice. Similarly, levels of the Th1 cytokines IFN-γ and IL-2 increased in WT and TG mice, but were 7.7- and 1.7-fold higher in TG mice. The characteristic shift towards Th2 cytokines was observed during infection in both WT and TG mice, with increased levels of IL-10 and IL-4 at day-14. The current data are in accordance with our previous in vitro findings showing that hGIIA kills parasites by releasing toxic lipids from oxidized lipoproteins. They further show that hGIIA sPLA2 is induced during mouse experimental malaria and has a protective in vivo role, lowering parasitaemia by likely releasing toxic lipids from oxidized lipoproteins but also indirectly by promoting a more sustained innate immune response.
Highlights
Malaria is a tropical and sub-tropical disease caused by a protozoan parasite of the genusPlasmodium, which is transmitted to humans by the bite of Anopheles mosquitoes [1]
We previously showed that injection of recombinant human group IIA secreted phospholipase A2 to Plasmodium chabaudi-infected mice lowers parasitaemia by 20%
The level of Human group IIA (hGIIA) secreted PLA2s (sPLA2s) was found to be increased in the 489 plasma of patients with malaria [47, 48, 54, 75] but its role was unclear
Summary
Malaria is a tropical and sub-tropical disease caused by a protozoan parasite of the genusPlasmodium, which is transmitted to humans by the bite of Anopheles mosquitoes [1]. Plasmodium species have been identified in humans Most malaria cases (93%) were in the World Health Organization (WHO) African Region, where P. falciparum is the most prevalent malaria parasite. A better understanding of malaria pathophysiology is key to open new perspectives to fight against Plasmodium infection. Among the various mechanisms of innate immunity and host response engaged following infection [2,3,4], endogenous secreted phospholipases A2 (sPLA2s) may play a specific role. Mammalian phospholipases A2 (PLA2, EC 3.1.1.4) comprise numerous intracellular and secreted enzymes that catalyze the hydrolysis of phospholipids at the sn-2 position to release free fatty acids and lysophospholipids [5, 6]. Most sPLA2s contribute to multiple pathophysiological functions by hydrolysis of various phospholipid substrates from cellular membranes or extracellular lipid components, such as lipoproteins, microparticles, lung surfactant, mitochondria, lipid diet and microbes [10, 12,13,14,15,16,17,18,19]
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