Fz2 and cdc42 mediate melanization and actin polymerization but are dispensable for Plasmodium killing in the mosquito midgut.
Fz2 and cdc42 mediate melanization and actin polymerization but are dispensable for Plasmodium killing in the mosquito midgut.
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DOI：
10.1371/journal.ppat.0020133
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发表时间：
2006-12
期刊：
影响因子：
6.7
通讯作者：
Levashina EA
中科院分区：
文献类型：
--
作者：
Shiao SH;Whitten MM;Zachary D;Hoffmann JA;Levashina EA
疟蚊媒介按蚊的中肠上皮是疟原虫的敌对环境，大多数寄生虫屈服于宿主的防御。本研究探讨了与贝氏疟原虫侵入冈比亚按蚊中肠相关的形态学和超微结构特征，以确定寄生虫杀死的位置和可能的机制。我们通过透射电镜和免疫荧光显示，大多数卵母细胞在细胞外空间被杀死。死亡或垂死的卵母细胞被邻近宿主上皮细胞的基细胞质内形成的聚合肌动蛋白区所包围。在难处理菌株蚊子中，我们发现该区域的形成与导致黑化的酚氧化酶活化密切相关。此外，我们确定了控制这两种现象的两个因素：跨膜受体卷曲-2和鸟苷三磷酸结合蛋白细胞分裂周期42。然而，双链RNA抑制对肌动蛋白聚合和黑化的破坏并不影响卵母细胞的存活。我们的研究结果将冈比亚拟虫杀灭寄生虫的机制从随后的反应中分离出来，这些反应表现为肌动蛋白聚合和酚氧化酶原活化。鼠模型。这些后一种过程让人想起其他生物体的伤口愈合，我们认为它们代表了一种针对垂死的卵胞体的伤口愈合反应，这被认为是受损组织。一段危险的旅程等待着疟疾——被蚊子吞食的疟原虫。大多数寄生虫在中肠被宿主反应消灭，在抗寄生虫的耐药蚊株中，死亡率可达100%。这种中肠“瓶颈”是通过对野生蚊子进行遗传控制来减少疟疾传播的一个有吸引力的目标。然而，其杀伤机制尚不清楚。在本研究中，电子显微镜分析跟踪了整个蚊子中肠入侵过程，以确定疟原虫杀死的主要部位和超微结构特征。作者发现，入侵可分为两个步骤：快速通过中肠细胞，然后在基底细胞外空间建立寄生虫，在那里它成为可溶性免疫因子破坏的重要目标。在难耐性蚊子中，死亡的寄生虫与邻近中肠细胞中肌动蛋白无细胞器区形成和寄生虫表面黑色素沉积有关。作者确定了控制这些现象的两个基因，分别是卷曲2号和细胞分裂周期42号。肌动蛋白带的形成和黑化通常被认为是杀伤机制；然而，作者通过基因沉默表明，这两种方法对疟原虫都是致命的。相反，这些机制可能代表了蚊子伤口愈合反应的一种形式，这种反应是由垂死寄生虫的存在引发的。
The midgut epithelium of the mosquito malaria vector Anopheles is a hostile environment for Plasmodium, with most parasites succumbing to host defenses. This study addresses morphological and ultrastructural features associated with Plasmodium berghei ookinete invasion in Anopheles gambiae midguts to define the sites and possible mechanisms of parasite killing. We show by transmission electron microscopy and immunofluorescence that the majority of ookinetes are killed in the extracellular space. Dead or dying ookinetes are surrounded by a polymerized actin zone formed within the basal cytoplasm of adjacent host epithelial cells. In refractory strain mosquitoes, we found that formation of this zone is strongly linked to prophenoloxidase activation leading to melanization. Furthermore, we identify two factors controlling both phenomena: the transmembrane receptor frizzled-2 and the guanosine triphosphate–binding protein cell division cycle 42. However, the disruption of actin polymerization and melanization by double-stranded RNA inhibition did not affect ookinete survival. Our results separate the mechanisms of parasite killing from subsequent reactions manifested by actin polymerization and prophenoloxidase activation in the A. gambiae–P. berghei model. These latter processes are reminiscent of wound healing in other organisms, and we propose that they represent a form of wound-healing response directed towards a moribund ookinete, which is perceived as damaged tissue. A dangerous journey awaits malaria Plasmodium parasites ingested by a mosquito. Most parasites are destroyed by host responses in the midgut, and in parasite-resistant refractory strains of mosquito the mortality can reach 100%. This midgut “bottleneck” represents an appealing target for reducing malaria transmission by the genetic control of wild mosquitoes. However, the killing mechanisms are still unclear. In this study, electron microscopical analyses followed the entire midgut invasion process in mosquitoes to identify the major site(s) and ultrastructural features of Plasmodium killing. The authors found that invasion can be divided into two steps: a swift passage through a midgut cell, followed by establishment of the parasite in the basal extracellular space, where it becomes an important target for destruction by soluble immunity factors. In refractory mosquitoes, dead parasites are associated with the formation of organelle-free zones of actin in adjacent midgut cells, and melanin deposition on the parasite surface. The authors identify two genes, called frizzled-2 and cell division cycle 42, that control these phenomena. Actin zone formation and melanization are generally thought to be killing mechanisms; however, the authors show by gene silencing that neither is lethal to Plasmodium. Instead, these mechanisms may represent a form of mosquito wound-healing response that is triggered by the presence of a moribund parasite.
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