The Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia.
Infect Immun. 2014 Mar;82(3):924-36. doi: 10.1128/IAI.00866-13. Epub 2013 Nov 11.
Plasmodium falciparum causes malaria disease during the asexual blood stages of infection when merozoites invade erythrocytes and replicate. Merozoite surface proteins (MSPs) are proposed to play a role in the initial binding of merozoites to erythrocytes, but precise roles remain undefined. Based on electron microscopy studies of invading Plasmodium merozoites, it is proposed that the majority of MSPs are cleaved and shed from the surface during invasion, perhaps to release receptor-ligand interactions. In this study, we demonstrate that there is not universal cleavage of MSPs during invasion. Instead, there is sequential and coordinated cleavage and shedding of proteins, indicating a diversity of roles for surface proteins during and after invasion. While MSP1 and peripheral surface proteins such as MSP3, MSP7, serine repeat antigen 4 (SERA4), and SERA5 are cleaved and shed at the tight junction between the invading merozoite and erythrocyte, the glycosylphosphatidylinositol (GPI)-anchored proteins MSP2 and MSP4 are carried into the erythrocyte without detectable processing. Following invasion, MSP2 rapidly degrades within 10 min, whereas MSP4 is maintained for hours. This suggests that while some proteins that are shed upon invasion may have roles in initial contact steps, others function during invasion and are then rapidly degraded, whereas others are internalized for roles during intraerythrocytic development. Interestingly, anti-MSP2 antibodies did not inhibit invasion and instead were carried into erythrocytes and maintained for approximately 20 h without inhibiting parasite development. These findings provide new insights into the mechanisms of invasion and knowledge to advance the development of new drugs and vaccines against malaria.
恶性疟原虫在无性血期感染时会引起疟疾，此时裂殖子侵入红细胞并进行复制。裂殖子表面蛋白（MSP）被认为在裂殖子最初与红细胞结合中发挥作用，但确切的作用仍未确定。基于对入侵恶性疟原虫的电子显微镜研究，提出大多数 MSP 在入侵过程中被切割和脱落表面，也许是为了释放受体 - 配体相互作用。在这项研究中，我们证明并非所有 MSP 在入侵过程中都被普遍切割。相反，存在蛋白质的顺序和协调切割和脱落，表明表面蛋白在入侵过程中和入侵后具有多种作用。虽然 MSP1 和外周表面蛋白（如 MSP3、MSP7、丝氨酸重复抗原 4（SERA4）和 SERA5）在入侵裂殖子和红细胞之间的紧密连接处被切割和脱落，但糖基磷脂酰肌醇（GPI）锚定蛋白 MSP2 和 MSP4 被带入红细胞而没有可检测到的处理。入侵后，MSP2 在 10 分钟内迅速降解，而 MSP4 则持续数小时。这表明，虽然一些在入侵时脱落的蛋白质可能在初始接触步骤中发挥作用，但其他蛋白质在入侵过程中发挥作用，然后迅速降解，而其他蛋白质则被内化以在红细胞内发育过程中发挥作用。有趣的是，抗 MSP2 抗体不会抑制入侵，反而会被带入红细胞并在不抑制寄生虫发育的情况下维持约 20 小时。这些发现为入侵机制提供了新的见解，并为开发针对疟疾的新药和疫苗提供了知识。
