Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature.
Release of hepatic Plasmodium yoelii merozoites into the pulmonary microvasculature.
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DOI：
10.1371/journal.ppat.0030171
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发表时间：
2007-11
期刊：
影响因子：
6.7
通讯作者：
Frevert U
中科院分区：
文献类型：
--
作者：
Baer K;Klotz C;Kappe SH;Schnieder T;Frevert U
疟原虫在侵入红细胞之前在肝脏中经历一轮增殖，并开始疟疾感染的症状性血液阶段。子孢子对肝细胞的感染可产生数千个裂殖子，这些裂殖子可侵入红细胞。裂殖子从受感染的肝细胞释放为裂体，裂体是被宿主细胞膜包围的数百个寄生虫的包。表达绿色荧光蛋白的约氏疟原虫的活体显微镜显示，大多数裂殖体完整地离开肝脏，大小相对均匀，为12-18 μm，含有100-200个裂殖子。裂粒体在随后通过右心的过程中完好无损地存活下来，并积聚在肺中。从左心室收集的血液和尾静脉血液中不存在裂体，表明肺有效地清除了血液中所有大的寄生虫聚集体。因此，在主要器官如脑、肾和脾中未检测到裂殖体。膜联蛋白V未能标记从肝流出物收集的裂体，表明磷脂酰丝氨酸未暴露在裂体膜的表面上，表明感染的肝细胞在裂体释放之前未经历细胞凋亡。裂殖体裂殖子继续表达绿色荧光蛋白，并且不掺入碘化丙啶或YO-PRO-1，表明寄生虫存活力和完整的裂殖体膜。裂殖体裂殖子感染性的证据由含有裂殖体的肝流出物提供，其比具有相同的低水平寄生虫血症的血液显著更具感染性。离体分析表明，裂殖体最终在肺毛细血管内解体，从而将裂殖子释放到血流中。我们的结论是，裂殖体包装保护肝脏裂殖子免受窦状库普弗细胞的吞噬攻击，并且释放到肺微血管系统中增加了红细胞成功入侵的机会。我们相信，疟原虫生命周期中这一以前未知的部分确保了疟疾感染从肝脏到血液阶段的有效过渡。疟疾寄生虫疟原虫在生命周期的血液阶段开始之前在肝脏中经历一轮大的繁殖，这一阶段导致典型的发热和寒战发作。使用活体显微镜和荧光寄生虫，我们研究了寄生虫从肝脏释放的模式和动力学，这是疟疾生命周期的关键阶段。早期的研究表明，受感染的肝细胞可以释放数十到数百包被宿主细胞膜包裹的寄生虫，这种结构现在被称为裂体。我们在这里报告说，这是寄生虫从肝脏释放的主要机制。宿主来源的裂体膜缺乏吞噬细胞吞噬的标志物，因此允许安全通过库普弗细胞（高活性肝巨噬细胞）的手套。裂体在通过心脏的过程中保持完整，并被隔离在肺毛细血管内，在那里膜最终崩解，释放寄生虫进入肺循环。我们认为，疟原虫生命周期的这一先前未知的部分促进了红细胞入侵，从而启动了生命周期的血液阶段和临床疟疾的发病。
Plasmodium undergoes one round of multiplication in the liver prior to invading erythrocytes and initiating the symptomatic blood phase of the malaria infection. Productive hepatocyte infection by sporozoites leads to the generation of thousands of merozoites capable of erythrocyte invasion. Merozoites are released from infected hepatocytes as merosomes, packets of hundreds of parasites surrounded by host cell membrane. Intravital microscopy of green fluorescent protein–expressing P. yoelii parasites showed that the majority of merosomes exit the liver intact, adapt a relatively uniform size of 12–18 μm, and contain 100–200 merozoites. Merosomes survived the subsequent passage through the right heart undamaged and accumulated in the lungs. Merosomes were absent from blood harvested from the left ventricle and from tail vein blood, indicating that the lungs effectively cleared the blood from all large parasite aggregates. Accordingly, merosomes were not detectable in major organs such as brain, kidney, and spleen. The failure of annexin V to label merosomes collected from hepatic effluent indicates that phosphatidylserine is not exposed on the surface of the merosome membrane suggesting the infected hepatocyte did not undergo apoptosis prior to merosome release. Merosomal merozoites continued to express green fluorescent protein and did not incorporate propidium iodide or YO-PRO-1 indicating parasite viability and an intact merosome membrane. Evidence of merosomal merozoite infectivity was provided by hepatic effluent containing merosomes being significantly more infective than blood with an identical low-level parasitemia. Ex vivo analysis showed that merosomes eventually disintegrate inside pulmonary capillaries, thus liberating merozoites into the bloodstream. We conclude that merosome packaging protects hepatic merozoites from phagocytic attack by sinusoidal Kupffer cells, and that release into the lung microvasculature enhances the chance of successful erythrocyte invasion. We believe this previously unknown part of the plasmodial life cycle ensures an effective transition from the liver to the blood phase of the malaria infection. The malaria parasite Plasmodium undergoes one large round of multiplication in the liver before beginning the blood phase of the life cycle, the phase that causes the typical episodes of fever and chills. Using intravital microscopy and fluorescent parasites, we studied the mode and dynamics of parasite release from the liver, a critical stage in the malaria life cycle. Earlier work had indicated that infected liver cells could release packets of dozens to hundreds of parasites enveloped by host cell membrane, structures now known as merosomes. We report here that this is the predominant mechanism of parasite release from the liver. The host-derived merosome membrane lacks a marker for phagocytic engulfment, thus allowing safe passage through the gauntlet of Kupffer cells, highly active liver macrophages. Merosomes remain intact during passage through the heart and become sequestered within lung capillaries where the membrane eventually disintegrates liberating the parasites into the lung circulation. We propose that this previously unknown part of the life cycle of Plasmodium facilitates red blood cell invasion, thus jump-starting the blood phase of the life cycle and the onset of clinical malaria.
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DOI：
10.1016/0035-9203(55)90042-0
发表时间：
1955-01-01
期刊：
TRANS ROY SOC TROP MED AND HYG
影响因子：
--
作者：
GARNHAM, P. C. C.;BRAY, R. S.;WILLIAMSON, J.
通讯作者：
WILLIAMSON, J.
影响因子：
4.4
作者：
Doolan, DL;Hoffman, SL
通讯作者：
Hoffman, SL
影响因子：
3.3
作者：
Conhaim, RL;Rodenkirch, LA
通讯作者：
Rodenkirch, LA
影响因子：
1.5
作者：
Franke-Fayard, B;Trueman, H;Janse, CJ
通讯作者：
Janse, CJ
影响因子：
1.5
作者：
Hugel, FU;Pradel, G;Frevert, U
通讯作者：
Frevert, U