The AMA1-RON complex drives Plasmodium sporozoite invasion in the mosquito and mammalian hosts.
The AMA1-RON complex drives Plasmodium sporozoite invasion in the mosquito and mammalian hosts.
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DOI：
10.1371/journal.ppat.1010643
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发表时间：
2022-06
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影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
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由吸血雌性按蚊传播的疟原虫子孢子侵入肝细胞进行初始一轮的细胞内复制，导致裂殖子的释放，裂殖子侵入红细胞并在红细胞内繁殖。子孢子和裂殖子共有许多在两个阶段表达的蛋白质，包括顶膜抗原1（AMA 1）和棒状颈蛋白（RONs）。虽然AMA 1和RONs是必需的裂殖子入侵红细胞在无性血液阶段复制的寄生虫，他们的子孢子的功能仍然不清楚。在这里，我们表明，AMA 1与RON在成熟的子孢子相互作用。通过在伯氏疟原虫中使用DiCre介导的条件基因缺失，我们证明子孢子中AMA 1、RON 2或RON 4的缺失损害蚊子唾液腺的定殖和哺乳动物肝细胞的侵袭，而不影响跨细胞寄生虫迁移。三维电子显微镜观察结果表明，子孢子通过环状结构和短暂的空泡进入唾液腺细胞。功能性AMA 1-罗恩复合物的缺乏导致入口连接的形态改变，与上皮细胞损伤相关。我们的数据证实，AMA 1和RON促进宿主细胞入侵疟原虫入侵阶段，并表明子孢子使用AMA 1-罗恩复合物有效和安全地进入蚊子唾液腺，以确保成功的寄生虫传播。这些结果打开了靶向AMA 1-罗恩复合物用于传播阻断抗疟策略的可能性。疟疾是由疟原虫寄生虫引起的，由蚊子传播。被称为子孢子的寄生虫的感染阶段定殖在蚊子的唾液腺中，当昆虫探测皮肤以吸血时，子孢子被注射到宿主体内。子孢子迅速迁移到宿主肝脏，侵入肝细胞并分化成下一个侵入形式，裂殖子，裂殖子侵入红细胞内并在红细胞内复制。裂殖子通过一种特殊的结构侵入细胞，这种结构被称为移动连接，由称为AMA 1和RON的蛋白质形成。这些蛋白质在子孢子中的作用尚不清楚。在这里，我们在啮齿动物疟疾模型中使用条件基因组编辑来产生AMA 1和RON缺陷的子孢子。突变体的表型分析显示，子孢子使用AMA 1-罗恩复合物两次，首先在蚊子中安全进入唾液腺并确保成功的寄生虫传播，然后在哺乳动物宿主肝脏中建立复制生态位。我们的数据表明，AMA 1和RON促进宿主细胞在疟原虫入侵阶段的入侵，并可能成为阻断传播的抗疟策略的潜在靶点。
Plasmodium sporozoites that are transmitted by blood-feeding female Anopheles mosquitoes invade hepatocytes for an initial round of intracellular replication, leading to the release of merozoites that invade and multiply within red blood cells. Sporozoites and merozoites share a number of proteins that are expressed by both stages, including the Apical Membrane Antigen 1 (AMA1) and the Rhoptry Neck Proteins (RONs). Although AMA1 and RONs are essential for merozoite invasion of erythrocytes during asexual blood stage replication of the parasite, their function in sporozoites was still unclear. Here we show that AMA1 interacts with RONs in mature sporozoites. By using DiCre-mediated conditional gene deletion in P. berghei, we demonstrate that loss of AMA1, RON2 or RON4 in sporozoites impairs colonization of the mosquito salivary glands and invasion of mammalian hepatocytes, without affecting transcellular parasite migration. Three-dimensional electron microscopy data showed that sporozoites enter salivary gland cells through a ring-like structure and by forming a transient vacuole. The absence of a functional AMA1-RON complex led to an altered morphology of the entry junction, associated with epithelial cell damage. Our data establish that AMA1 and RONs facilitate host cell invasion across Plasmodium invasive stages, and suggest that sporozoites use the AMA1-RON complex to efficiently and safely enter the mosquito salivary glands to ensure successful parasite transmission. These results open up the possibility of targeting the AMA1-RON complex for transmission-blocking antimalarial strategies. Malaria is caused by Plasmodium parasites, which are transmitted by mosquitoes. Infectious stages of the parasite known as sporozoites colonize the mosquito salivary glands and are injected into the host when the insect probes the skin for blood feeding. Sporozoites rapidly migrate to the host liver, invade hepatocytes and differentiate into the next invasive forms, the merozoites, which invade and replicate inside red blood cells. Merozoites invade cells through a specialized structure, known as the moving junction, formed by proteins called AMA1 and RONs. The role of these proteins in sporozoites remains unclear. Here we used conditional genome editing in a rodent malaria model to generate AMA1- and RON-deficient sporozoites. Phenotypic analysis of the mutants revealed that sporozoites use the AMA1-RON complex twice, first in the mosquito to safely enter the salivary glands and ensure successful parasite transmission, then in the mammalian host liver to establish a replicative niche. Our data establish that AMA1 and RONs facilitate host cell invasion across Plasmodium invasive stages, and might represent potential targets for transmission-blocking antimalarial strategies.
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影响因子：
48
作者：
Andenmatten, Nicole;Egarter, Saskia;Jackson, Allison J;Jullien, Nicolas;Herman, Jean-Paul;Meissner, Markus
通讯作者：
Meissner, Markus
影响因子：
7
作者：
Lindner, Scott E.;Swearingen, Kristian E.;Kappe, Stefan H. I.
通讯作者：
Kappe, Stefan H. I.
影响因子：
28.3
作者：
Guerin, Amandine;Corrales, Rosa Milagros;Lebrun, Maryse
通讯作者：
Lebrun, Maryse
影响因子：
56.9
作者：
Mota, MM;Pradel, G;Rodríguez, A
通讯作者：
Rodríguez, A
DOI：
10.1073/pnas.95.3.1230
发表时间：
1998-02-03
影响因子：
11.1
作者：
Kappe, SHI;Noe, AR;Adams, JH
通讯作者：
Adams, JH