Plasmodium falciparum gametocytogenesis

描述（由申请人提供）：对于通过蚊子在人与人之间传播的疟疾，疟原虫寄生虫必须经历性别分化以形成配子体。虽然是生命周期的重要组成部分，但对体外或体内这些阶段的产生知之甚少，这使得有效阻断传播的策略的开发变得复杂。在上一个资助期，我们确定了一个对配子体产生至关重要的基因，即恶性疟原虫配子体发育1（Pfgdv1）和一组在恶性疟原虫早期配子体发生过程中特异表达的基因（Pfge基因）。这些基因在体外和一组疟疾感染患者中的表达谱的分析导致以下假设：配子体在每个无性周期期间形成，作为正常发育的一部分。这种持续的配子体生产将在蚊子叮咬时提供持续的传染性寄生虫来源。然而，它也对控制措施的设计产生了严重影响，并表明需要大规模治疗或接种疫苗来消除寄生虫。为了进一步评估体内配子体发生的起始，我们开发了一种方法来直接比较患者血液样本中的无性寄生虫血症和配子体定型。配子体诱导和成熟之间的关系，在体内需要了解的因素，有助于生产感染性配子体。目标1将评价患者年龄和红细胞压积在配子体产生中的作用，而目标2和3将使用分子学（目标2）和免疫学（目标3）来了解寄生虫暴露和免疫刺激对配子体定型和成熟的作用。这项实地工作将补充我们正在进行的基础研究，确定配子体发生的分子基础。这项工作将扩大我们对疟疾传播所必需的配子母细胞的启动和形成的理解。这些发现应该提供标记物，以在配子体载体具有传染性之前识别它们，并识别可以靶向阻断传播的信号通路。

DESCRIPTION (provided by applicant): For malaria to be spread from person to person via a mosquito, Plasmodium parasites must undergo sexual differentiation to form gametocytes. Although an essential part of the life cycle, little is known about the production of these stages n vitro or in vivo, which complicates the development of strategies that effectively block transmission. In the previous funding period we identified a gene that is critical for gametocyte production, P. falciparum gametocyte development 1 (Pfgdv1) and the set of genes specifically expressed during early gametocytogenesis in P. falciparum (Pfge genes). Analysis of the expression profiles of these genes in vitro and in a cohort of malaria infected patients lead to th hypothesis that gametocytes are formed during each asexual cycle as part of normal development. This type of continuous gametocyte production would provide a consistent source of infectious parasites whenever a mosquito bites. However, it also has serious implications for the design of control measures and suggests that mass treatment or vaccination would be needed to eliminate the parasite. To further evaluate the initiation of gametocytogenesis in vivo, we developed a method to directly compare asexual parasitemia and gametocyte commitment in blood samples from patients. The relationship between gametocyte induction and maturation in vivo is needed to understand the factors that contribute to the production of infectious gametocytes. Aim one will evaluate the role of patient age and hematocrit in gametocyte production, while Aims 2 and 3 will use molecular (Aim 2) and immunological (Aim 3) to understand the role of parasite exposure and immune stimulation on gametocyte commitment and maturation. This field work will complement our ongoing basic research defining the molecular basis for gametocytogenesis. Together the work will extend our understanding of the initiation and formation gametocytes that are essential for the spread of malaria. The findings should provide markers to identify gametocyte carriers before they are infectious and identify signaling pathways that could be targeted to block transmission.