Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells.
Breakdown in membrane asymmetry regulation leads to monocyte recognition of P. falciparum-infected red blood cells.
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DOI：
10.1371/journal.ppat.1009259
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Maier AG
中科院分区：
文献类型：
--
作者：
Fraser M;Jing W;Bröer S;Kurth F;Sander LE;Matuschewski K;Maier AG
人类疟疾寄生虫恶性疟原虫依赖脂质生存;这使得其脂质代谢成为一个有吸引力的药物靶点。脂质磷脂酰丝氨酸（PS）通常局限于红细胞膜（RBC）双层的内小叶;然而，一些研究表明，细胞内寄生虫感染导致这种脂质存在于RBC膜外小叶，在那里它可以作为吞噬细胞的识别信号。在这里，我们使用荧光脂质类似物和探针来研究负责维持膜小叶之间的不对称性的酶反应，并发现在寄生的RBC中，膜不对称性的维持被部分破坏，并且PS在外小叶中增加。我们使用荧光染料和探针研究了未感染和感染RBC之间差异的根本原因，发现感染RBC细胞质中的钙水平增加，而膜胆固醇从红细胞质膜中耗尽。我们探讨了PS暴露对单核细胞增强吞噬作用的影响，并表明感染的RBC必须消耗能量以限制吞噬细胞识别，并提供了PS暴露有助于恶性疟原虫感染的RBC的吞噬识别的实验证据。总之，这些发现强调了PS暴露在恶性疟原虫感染的红细胞表面与宿主免疫系统在体内相互作用的关键作用，并提供了有针对性的抗疟药物设计的理由。疟疾仍然是世界上最致命的寄生虫病，尽管经过多年的持续努力，新药开发以及对寄生虫及其与宿主相互作用的更深入了解。我们研究了一系列相互关联的过程，从脂质和钙螯合到免疫细胞的识别。我们在这里表明，胆固醇和钙离子的摄取引起的变化，寄生的宿主红细胞。这些变化影响宿主细胞中脂质转运酶的活性，这些酶将某些磷脂保持在膜的特定侧：一个称为膜不对称的概念。我们发现，寄生虫引起激活钙和胆固醇敏感的酶，scramblase，所以磷脂是来回乱。因此，脂质磷脂酰丝氨酸暴露在膜外层，作为“吃我”的信号，包括单核细胞的吞噬细胞。在整个研究过程中，我们发现受感染的细胞正在消耗能量来补偿最终导致吞噬作用的过程。但是，尽管有这些补偿过程，一部分寄生虫还是被单核细胞摄取。我们对这一途径的系统探索解决了过去报告中相互矛盾的发现，并暴露了寄生虫代谢中的漏洞，这些漏洞可用于靶向药物设计。
The human malaria parasite Plasmodium falciparum relies on lipids to survive; this makes its lipid metabolism an attractive drug target. The lipid phosphatidylserine (PS) is usually confined to the inner leaflet of the red blood cell membrane (RBC) bilayer; however, some studies suggest that infection with the intracellular parasite results in the presence of this lipid in the RBC membrane outer leaflet, where it could act as a recognition signal to phagocytes. Here, we used fluorescent lipid analogues and probes to investigate the enzymatic reactions responsible for maintaining asymmetry between membrane leaflets, and found that in parasitised RBCs the maintenance of membrane asymmetry was partly disrupted, and PS was increased in the outer leaflet. We examined the underlying causes for the differences between uninfected and infected RBCs using fluorescent dyes and probes, and found that calcium levels increased in the infected RBC cytoplasm, whereas membrane cholesterol was depleted from the erythrocyte plasma membrane. We explored the resulting effect of PS exposure on enhanced phagocytosis by monocytes, and show that infected RBCs must expend energy to limit phagocyte recognition, and provide experimental evidence that PS exposure contributes to phagocytic recognition of P. falciparum-infected RBCs. Together, these findings underscore the pivotal role for PS exposure on the surface of Plasmodium falciparum-infected erythrocytes for in vivo interactions with the host immune system, and provide a rationale for targeted antimalarial drug design. Malaria remains the deadliest parasitic disease in the world despite years of sustained effort, new drug development, and a greater understanding of the parasite and its interactions with its host. We examined a series of interconnected processes, from lipid and calcium sequestration through to recognition by immune cells. We show here that the uptake of cholesterol and calcium ions induce changes to the parasitised host red blood cell. These changes affect the activity of lipid-transporting enzymes in the host cell, which keep certain phospholipids on specific sides of the membrane: a concept called membrane asymmetry. We show that the parasite causes activation of a calcium- and cholesterol-sensitive enzyme, scramblase, so phospholipids are scrambled back and forth. Therefore, the lipid phosphatidylserine becomes exposed in the membrane outer layer, acting as an ‘eat me’ signal to phagocytes including monocytes. Throughout our study, we show that the infected cell is expending energy to compensate for the processes which ultimately lead to phagocytosis. But despite these compensatory processes, a portion of parasites are ingested by monocytes. Our systematic exploration of this pathway addresses contradictory findings from past reports, and exposes vulnerabilities in the parasite’s metabolism that could be used for targeted drug design.
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