Molecular and immunologic roles of P. falciparum invasion ligand polymorphisms

恶性疟原虫侵袭配体多态性的分子和免疫学作用

• 批准号: 7674449
• 负责人: Amy Kristine Bei
• 金额: $ 3.32万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674449
• 关键词: Molecular; immunologic; roles; P.; falciparum

DESCRIPTION (provided by applicant): Plasmodium falciparum is the causative agent of the severest manifestation of human malaria. A unique characteristic of Plasmodium falciparum which allows it to cause such virulent disease is its ability to differentially utilize members of multi-gene families that are involved in the processes of cytoadherence and invasion. Variant expression of the Plasmodium falciparum Reticulocyte Binding Protein Homolog (PfRh) invasion ligands has been associated with alternative invasion pathways through differential erythrocyte receptor binding. We hypothesize that variant expression, in addition to parasite polymorphism in these critical invasion ligands, provides the parasite with a mechanism to adapt to different host environments as well as to evade immune responses. We have shown that naturally acquired immune responses exist which recognize the PfRh proteins and specific domains. We have also previously identified polymorphisms in these proteins which have been associated with altered invasion phenotype. The aim of this study is to generate transgenic parasite lines which will allow us to precisely address the contribution of domains and naturally occurring polymorphic alleles of the PfRh ligands on invasion, in the presence of polymorphic erythrocyte receptors or inhibitory antibodies. PUBLIC HEALTH RELEVANCE: The proposed research will provide a greater understanding of selective pressures which lead to emergence of polymorphic parasite genes, knowledge which could greatly inform both anti- malarial drug and vaccine design. Further, this research will contribute a detailed study of inhibitory immune responses raised against a family of invasion ligands which could be potential vaccine candidate antigens. Taken together, the aims of this study should provide valuable information as to the dynamics of parasite-host interactions in a disease endemic setting, and such information is critical when making and implementing malaria prevention and treatment policies.

描述（由申请人提供）：恶性疟原虫是人类疟疾最严重表现的病原体。恶性疟原虫能够引起这种致命性疾病的一个独特特征是它能够差异化地利用参与细胞粘附和侵袭过程的多基因家族成员。恶性疟原虫网织红细胞结合蛋白同源物 (PfRh) 入侵配体的变异表达与通过差异红细胞受体结合的替代入侵途径相关。我们假设，除了这些关键入侵配体中的寄生虫多态性之外，变异表达还为寄生虫提供了适应不同宿主环境以及逃避免疫反应的机制。我们已经证明，存在识别 PfRh 蛋白和特定结构域的自然获得性免疫反应。我们之前还发现了这些蛋白质的多态性，这些多态性与入侵表型的改变有关。本研究的目的是产生转基因寄生虫系，这将使我们能够在多态性红细胞受体或抑制性抗体存在的情况下精确解决 PfRh 配体的结构域和自然发生的多态性等位基因对入侵的贡献。 公共卫生相关性：拟议的研究将提供对导致多态性寄生虫基因出现的选择压力的更深入的了解，这些知识可以为抗疟疾药物和疫苗设计提供极大的信息。此外，这项研究将有助于详细研究针对入侵配体家族产生的抑制性免疫反应，这些配体可能是潜在的疫苗候选抗原。总而言之，这项研究的目的应提供有关疾病流行环境中寄生虫与宿主相互作用动态的有价值的信息，这些信息在制定和实施疟疾预防和治疗政策时至关重要。