Plasmodium Cysteine Repeat Modular Proteins 3 and 4 are essential for malaria parasite transmission from the mosquito to the host
Plasmodium Cysteine Repeat Modular Proteins 3 and 4 are essential for malaria parasite transmission from the mosquito to the host
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DOI：
10.1186/1475-2875-10-71
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发表时间：
2011-03-31
期刊：
影响因子：
3
通讯作者：
Thompson, Joanne
中科院分区：
文献类型：
--
作者：
Douradinha, Bruno;Augustijn, Kevin D.;Thompson, Joanne
背景资料：疟原虫半胱氨酸重复模块蛋白（PCRMP）是疟原虫的四个保守蛋白家族，其包含许多涉及宿主-寄生虫相互作用的基序。对缺乏PCRMP 1或2表达的啮齿动物寄生虫伯氏疟原虫的突变体的分析表明，这些蛋白质对于伯氏疟原虫子孢子靶向蚊子唾液腺并因此从蚊子传播到小鼠是必需的。在这项工作中，剩余的PCRMP家族成员，PCRMP 3和4，通过产生和分析伯氏疟原虫基因缺失突变体pcrmp 3和pcrmp 4，研究了整个疟原虫生命周期。已经通过光学显微镜和电子显微镜以及通过体外HEPG 2细胞中肝脏阶段发育分析和通过用突变子孢子感染小鼠来评价了PCRMP成员在疟原虫生命周期的传播和肝脏阶段中的作用。此外，小鼠免疫活三角洲pcrmp 3和三角洲pcrmp 4子孢子，以评估其免疫潜力作为一种遗传减毒的寄生虫为基础的vaccine.Results：破坏的pcrmp 3和pcrmp 4在伯氏疟原虫揭示，他们也是必不可少的传播的寄生虫通过蚊子载体，虽然以不同的方式pbcrmp 1和2。缺乏PCRMP 3或PCRMP 4表达的突变体在蚊子中显示出正常的血液阶段发育和卵囊形成，并发育成形态学上正常的子孢子，但这些子孢子在从卵囊排出方面有缺陷，并且不进入唾液腺。从卵囊中提取的子孢子进行滑行运动并侵入和感染肝细胞，但不进行进一步的发育和增殖。此外，该研究表明，免疫与三角洲crmp 3和三角洲crmp 4子孢子不赋予保护性免疫后，随后的challenge.Conclusions：PCRMP 3和4在疟原虫的生命周期中发挥多种作用，他们是必不可少的子孢子感染蚊子唾液腺的建立，并随后在肝细胞中的发展。然而，尽管Delta pcrmp 3和Delta pcrmp 4寄生虫在肝脏中完全生长受损，但用活子孢子免疫不会诱导已显示用于其他遗传减毒寄生虫的保护性免疫应答。
Background: The Plasmodium Cysteine Repeat Modular Proteins (PCRMP) are a family of four conserved proteins of malaria parasites, that contain a number of motifs implicated in host-parasite interactions. Analysis of mutants of the rodent parasite Plasmodium berghei lacking expression of PCRMP1 or 2 showed that these proteins are essential for targeting of P. berghei sporozoites to the mosquito salivary gland and, hence, for transmission from the mosquito to the mouse.Methods: In this work, the role of the remaining PCRMP family members, PCRMP3 and 4, has been investigated throughout the Plasmodium life cycle by generation and analysis of P. berghei gene deletion mutants,.pcrmp3 and.pcrmp4. The role of PCRMP members during the transmission and hepatic stages of the Plasmodium lifecycle has been evaluated by light- and electron microscopy and by analysis of liver stage development in HEPG2 cells in vitro and by infecting mice with mutant sporozoites. In addition, mice were immunized with live Delta pcrmp3 and Delta pcrmp4 sporozoites to evaluate their immunization potential as a genetically-attenuated parasite-based vaccine.Results: Disruption of pcrmp3 and pcrmp4 in P. berghei revealed that they are also essential for transmission of the parasite through the mosquito vector, although acting in a distinct way to pbcrmp1 and 2. Mutants lacking expression of PCRMP3 or PCRMP4 show normal blood stage development and oocyst formation in the mosquito and develop into morphologically normal sporozoites, but these have a defect in egress from oocysts and do not enter the salivary glands. Sporozoites extracted from oocysts perform gliding motility and invade and infect hepatocytes but do not undergo further development and proliferation. Furthermore, the study shows that immunization with Delta crmp3 and Delta crmp4 sporozoites does not confer protective immunity upon subsequent challenge.Conclusions: PCRMP3 and 4 play multiple roles during the Plasmodium life cycle; they are essential for the establishment of sporozoite infection in the mosquito salivary gland, and subsequently for development in hepatocytes. However, although Delta pcrmp3 and Delta pcrmp4 parasites are completely growth-impaired in the liver, immunization with live sporozoites does not induce the protective immune responses that have been shown for other genetically-attenuated parasites.