Molecular and immunologic roles of P. falciparum invasion ligand polymorphisms

描述（由申请人提供）：恶性疟原虫是人类疟疾最严重表现形式的病原体。恶性疟原虫能够引起如此致命疾病的一个独特特征是，它能够不同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体（PfRh）入侵配体的变异表达与通过不同红细胞受体结合的其他入侵途径有关。我们假设，除了寄生虫在这些关键入侵配体中的多态性外，变异表达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，自然获得性免疫反应存在识别PfRh蛋白和特定结构域。我们之前也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，这将使我们能够精确地解决PfRh配体的结构域和自然存在的多态性等位基因在入侵时的贡献，在多态红细胞受体或抑制性抗体的存在下。

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.