Plasmodium falciparum gametocytogenesis

恶性疟原虫配子细胞发生

• 批准号: 8761439
• 负责人: Kim C Williamson
• 金额: $ 33.64万
• 依托单位: LOYOLA UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761439
• 关键词: Affect; Age; Antibodies; Appearance; Artemisinins; Basic Science; Biological Assay; Bite; Blood; Blood specimen; Cells; Cessation of life; Clinical; Combined Modality Therapy; Commit; Complement; Culicidae; DNA; Data; Development; Disease; Erythrocytes; Evaluation; Exposure to; Funding; Future; Genes; Genetic Transcription; Genotype; Giemsa stain; Goals; Harvest; Hematocrit procedure; Hemoglobin; Human; Immune; Immune response; Immunity; In Vitro; Individual; Infection; Integration Host Factors; Intervention; Invaded; Lead; Life Cycle Stages; Malaria; Measures; Methods; Molecular; Molecular Analysis; Molecular Profiling; Monitor; Nucleic Acids; Parasitemia; Parasites; Pathway interactions; Patient Monitoring; Patients; Pattern; Persons; Plasma; Plasmodium; Plasmodium falciparum; Population; Predictive Value; Prevalence; Production; RNA; Reporting; Role; Sampling; Signal Pathway; Source; Staging; System; Testing; Time; Vaccination; Work; artemisinine; asexual; base; cohort; cytokine; design; follow-up; in vivo; killings; public health relevance; tissue culture; transmission process

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.

描述（由申请人提供）：疟疾要通过蚊子在人与人之间传播，疟原虫必须经过性分化形成配子体。尽管这是生命周期的重要组成部分，但人们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制定变得复杂。在之前的资助期内，我们发现了一个对配子细胞产生至关重要的基因，恶性疟原虫配子细胞发育1 （Pfgdv1）和一组在恶性疟原虫配子细胞早期形成过程中特异性表达的基因（Pfge基因）。对这些基因在体外和疟疾感染患者队列中的表达谱的分析导致了配子细胞在每个无性周期中形成作为正常发育的一部分的假设。这种连续的配子体生产将在蚊子叮咬时提供一致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这种寄生虫。为了进一步评估体内配子细胞发生的起始，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，以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细胞产生中的作用，而目的二和目的三将使用分子（目的二）和免疫学（目的三）来了解寄生虫暴露和免疫刺激对配子细胞承诺和成熟的作用。这项野外工作将补充我们正在进行的定义配子细胞发生的分子基础的基础研究。总之，这项工作将扩大我们对配子体的起始和形成的理解，配子体对疟疾的传播至关重要。这一发现将提供在配子细胞具有传染性之前识别配子细胞携带者的标记物，并确定可能阻断传播的信号通路。