Plasmodium falciparum is the pathogen responsible for the most devastating form of human malaria. As it replicates asexually in the erythrocytes of its human host, the parasite feeds on haemoglobin uptaken from these cells. Heme, a toxic by-product of haemoglobin utilization by the parasite, is neutralized into inert hemozoin in the food vacuole of the parasite. Lipid homeostasis and phospholipid metabolism are crucial for this process, as well as for the parasite’s survival and propagation within the host. P. falciparum harbours a uniquely large family of phospholipases, which are suggested to play key roles in lipid metabolism and utilization. Here, we show that one of the parasite phospholipase (P. falciparum lysophospholipase, PfLPL1) plays an essential role in lipid homeostasis linked with the haemoglobin degradation and heme conversion pathway. Fluorescence tagging showed that the PfLPL1 in infected blood cells localizes to dynamic vesicular structures that traffic from the host-parasite interface at the parasite periphery, through the cytosol, to get incorporated into a large vesicular lipid rich body next to the food-vacuole. PfLPL1 is shown to harbour enzymatic activity to catabolize phospholipids, and its transient downregulation in the parasite caused a significant reduction of neutral lipids in the food vacuole-associated lipid bodies. This hindered the conversion of heme, originating from host haemoglobin, into the hemozoin, and disrupted the parasite development cycle and parasite growth. Detailed lipidomic analyses of inducible knock-down parasites deciphered the functional role of PfLPL1 in generation of neutral lipid through recycling of phospholipids. Further, exogenous fatty-acids were able to complement downregulation of PfLPL1 to rescue the parasite growth as well as restore hemozoin levels. We found that the transient downregulation of PfLPL1 in the parasite disrupted lipid homeostasis and caused a reduction in neutral lipids essentially required for heme to hemozoin conversion. Our study suggests a crucial link between phospholipid catabolism and generation of neutral lipids (TAGs) with the host haemoglobin degradation pathway.

中文翻译：

---

一种必需的囊泡运输磷脂酶介导中性脂质合成并有助于恶性疟原虫中的血红素形成

恶性疟原虫是造成人类疟疾最具破坏性的病原体。当它在人类宿主的红细胞中进行无性复制时，寄生虫以从这些细胞中摄取的血红蛋白为食。血红素是寄生虫利用血红蛋白的有毒副产物，在寄生虫的食物液泡中被中和成惰性血红素。脂质稳态和磷脂代谢对于这一过程以及寄生虫在宿主内的生存和繁殖至关重要。恶性疟原虫拥有一个独特的大家族磷脂酶，被认为在脂质代谢和利用中起关键作用。在这里，我们展示了一种寄生虫磷脂酶（恶性疟原虫溶血磷脂酶，PfLPL1）在与血红蛋白降解和血红素转化途径相关的脂质稳态中发挥重要作用。荧光标记表明，受感染血细胞中的 PfLPL1 定位于动态的囊泡结构，这些囊泡结构从寄生虫外围的宿主-寄生虫界面通过胞质溶胶进入食物液泡旁边的一个富含脂质的大囊泡体中。PfLPL1 显示出具有分解磷脂的酶活性，并且其在寄生虫中的短暂下调导致食物液泡相关脂质体中的中性脂质显着减少。这阻碍了源自宿主血红蛋白的血红素转化为血红素，并扰乱了寄生虫的发育周期和寄生虫的生长。可诱导敲除寄生虫的详细脂质组学分析破译了 PfLPL1 在通过磷脂循环产生中性脂质中的功能作用。此外，外源性脂肪酸能够补充 PfLPL1 的下调，以挽救寄生虫的生长并恢复血红素水平。我们发现寄生虫中 PfLPL1 的瞬时下调破坏了脂质稳态，并导致血红素向血红素转化所需的中性脂质减少。我们的研究表明，磷脂分解代谢和中性脂质 (TAG) 的产生与宿主血红蛋白降解途径之间存在重要联系。外源性脂肪酸能够补充 PfLPL1 的下调，以挽救寄生虫的生长并恢复 hemozoin 水平。我们发现寄生虫中 PfLPL1 的瞬时下调破坏了脂质稳态，并导致血红素向血红素转化所需的中性脂质减少。我们的研究表明，磷脂分解代谢和中性脂质 (TAG) 的产生与宿主血红蛋白降解途径之间存在重要联系。外源性脂肪酸能够补充 PfLPL1 的下调，以挽救寄生虫的生长并恢复 hemozoin 水平。我们发现寄生虫中 PfLPL1 的瞬时下调破坏了脂质稳态，并导致血红素向血红素转化所需的中性脂质减少。我们的研究表明，磷脂分解代谢和中性脂质 (TAG) 的产生与宿主血红蛋白降解途径之间存在重要联系。