UMR 7245 Molécules de Communication et Adaptation des Micro-organismes, Muséum National d'Histoire Naturelle, CNRS, CP52, 61 rue Buffon, Paris Cedex 05 75231, France.
Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR7275, Valbonne Sophia Antipolis, France.
Biochimie. 2021 Oct;189:120-136. doi: 10.1016/j.biochi.2021.06.009. Epub 2021 Jun 24.
We previously showed that injection of recombinant human group IIA secreted phospholipase A (hGIIA sPLA) to Plasmodium chabaudi-infected mice lowers parasitaemia by 20%. Here, we show that transgenic (TG) mice overexpressing hGIIA sPLA have a peak of parasitaemia about 30% lower than WT littermates. During infection, levels of circulating sPLA, 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 sPLA. 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 sPLA 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.
我们之前曾表明，向感染疟原虫（Plasmodium chabaudi）的小鼠注射重组人 IIA 组分泌型磷脂酶 A（hGIIA sPLA）可将寄生虫血症降低 20%。在这里，我们表明，过表达 hGIIA sPLA 的转基因（TG）小鼠的寄生虫血症峰值比 WT 同窝仔低约 30%。在感染过程中，循环 sPLA、酶活性和血浆脂质过氧化水平在寄生虫血症峰值的第 14 天达到最高。hGIIA mRNA 的水平在肝脏中增加，但在脾脏和血细胞中没有增加，这表明肝脏可能是循环 hGIIA sPLA 的来源。在感染前，TG 小鼠的白细胞和促炎细胞因子的基线水平高于 WT 同窝仔。感染后，中性粒细胞、淋巴细胞和单核细胞的数量增加，并在 WT 和 TG 小鼠的寄生虫血症峰值达到最大值，但在 TG 小鼠中更高。同样，Th1 细胞因子 IFN-γ 和 IL-2 的水平在 WT 和 TG 小鼠中增加，但在 TG 小鼠中增加了 7.7-和 1.7 倍。在 WT 和 TG 小鼠中均观察到向 Th2 细胞因子的特征性转变，在第 14 天 IL-10 和 IL-4 的水平增加。目前的数据与我们之前的体外研究结果一致，表明 hGIIA 通过从氧化脂蛋白中释放有毒脂质来杀死寄生虫。它们进一步表明，hGIIA sPLA 在小鼠实验性疟疾中被诱导，具有保护作用，通过从氧化脂蛋白中释放有毒脂质来降低寄生虫血症，但也通过间接促进更持续的先天免疫反应来实现。
