Molecular and immunologic roles of P. falciparum invasion ligand polymorphisms

描述(申请人提供)：恶性疟原虫是人类疟疾最严重表现的病原体。恶性疟原虫致病的一个独特特征是，它能够不同地利用参与细胞黏附和入侵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基因(PfRh)侵袭配体的变异表达与不同的侵袭途径有关，通过不同的红细胞受体结合。我们推测，除了这些关键入侵配体上的寄生虫多态外，变异表达还为寄生虫提供了一种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。我们以前也发现了这些蛋白的多态与侵袭表型的改变有关。这项研究的目的是建立转基因寄生虫系，使我们能够在存在多态红细胞受体或抑制性抗体的情况下，准确地定位PfRh配体的结构域和自然发生的多态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寄生虫基因多态出现的选择压力的更多了解，这些知识可以极大地为抗疟疾药物和疫苗设计提供信息。此外，这项研究将有助于详细研究针对一类可能成为疫苗候选抗原的侵袭配体家族所产生的抑制性免疫反应。综上所述，这项研究的目的应该提供关于疾病流行环境中寄生虫-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。

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.