Plasmodium falciparum gametocytogenesis

描述(申请人提供)：疟疾要通过蚊子在人与人之间传播，疟原虫必须经历性别分化才能形成配子体。尽管这些阶段是生命周期的重要组成部分，但对这些阶段在体外或体内的产生知之甚少，这使得有效阻断传播的策略的开发变得复杂。在之前的资助阶段，我们发现了一个对配子体产生至关重要的基因，恶性疟原虫配子体发育1(Pfgdv1)，以及恶性疟原虫配子体发生早期特异表达的一组基因(PFGE基因)。对这些基因在体外和一组疟疾感染患者中的表达情况的分析导致了这样的假设，即配子体是在每个无性周期中形成的，是正常发育的一部分。这种持续的配子体产生将在蚊子叮咬时提供一致的感染性寄生虫来源。然而，它也对控制措施的设计产生了严重影响，并建议需要进行大规模治疗或接种疫苗以消除寄生虫。为了进一步评估体内配子细胞生成的启动，我们开发了一种直接比较患者血液样本中无性寄生虫血症和配子细胞承诺的方法。需要了解体内配子体诱导和成熟之间的关系，才能了解导致感染性配子体产生的因素。目的一将评估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(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承诺和成熟的作用。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。这项工作将共同扩大我们对配子体启动和形成的理解，配子体对于疟疾的传播至关重要。这些发现应该提供标记，在配子体携带者具有感染性之前识别它们，并识别可能被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.