Variant surface antigens and immunity to malaria

变异表面抗原和对疟疾的免疫力

• 批准号: 7451034
• 负责人: James Matthew Burns
• 金额: $ 42.1万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7451034
• 关键词: Address; Adherence; Adhesions; Antibodies; Antigen Targeting; Area; Attention; B-Lymphocyte Epitopes; Binding; Blocking Antibodies; Blood; Blood Circulation; Blood Tests; Bone Marrow; Burn injury; Cells; Child; Data; Development; Environment; Erythrocyte Membrane; Erythrocytes; Erythropoiesis; Exposure to; Family; Genes; Genomics; Goals; Growth; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Invaded; Localized; Malaria; Malaria Vaccines; Measures; Mediating; Membrane Protein Gene; Membrane Proteins; Microarray Analysis; Modeling; Monitor; Multigene Family; Parasites; Peripheral; Plasmodium falciparum; Plasmodium vivax; Plasmodium yoelii; Process; Protein Binding; Proteins; Research Personnel; Reticulocytes; Rodent; Rodent Model; Role; Serum; Site; Spleen; Staging; Surface; Surface Antigens; Testing; Tissues; Tropism; Vaccine Design; Vaccines; Variant; Vascular Endothelial Cell; Vascular Endothelium; Vivax Malaria; base; erythrocyte receptor; genome sequencing; improved; in vivo; inhibiting antibody; merozoite surface protein; neutralizing antibody; novel; parasite invasion; peripheral blood; preference; pressure; prevent; programs; receptor; success; vaccine development

DESCRIPTION (provided by applicant): Much attention is focused on the development and testing of blood-stage malaria vaccines that target antigens expressed on the surface of merozoites (MSPs) given their functional importance in the invasion of erythrocytes and accessibility to serum antibodies. These efforts have been guided by in vitro studies of Plasmodium falciparum and in vivo studies of rodent malarial parasites that demonstrated the antibody- mediated inhibition of merozoite invasion of mature erythrocytes. However, data from studies of Plasmodium yoelii suggest that in vivo, these same antibodies are insufficient to prevent merozoites from invading reticulocytes. This does not appear to be due solely to differences in the receptors on host erythrocytes engaged by distinct merozoite proteins. This issue must be addressed if MSP-based vaccines are to be effective against Plasmodium vivax, a reticulocyte-restricted malaria parasite. Our hypothesis is that RBCs infected with reticulocyte-restricted malaria parasites localize to sites of erythropoiesis in vivo, mature and release merozoites into an environment that favors interaction with newly formed reticulocytes and reduces exposure to merozoite neutralizing antibodies. To test this hypothesis, we will conduct in vitro and vivo studies with P. yoelii blood-stage parasites that mimic the restricted or non-restricted host cell preferences of the human malarial parasites. We will focus on plasmodial proteins and variant surface antigens expressed on the reticulocyte surface, on their role in mediating adherence of pRBCs to vascular endothelium and on their role in immune evasion. Specifically, we will define the subset of plasmodial erythrocyte membrane protein genes expressed in P. yoelii infected reticulocytes which adhere to vascular endothelial cells and monitor changes in their expression in parasites under immune pressure. We will identify surface-exposed, P. yoelii reticulocyte membrane proteins that bind to receptors expressed on vascular endothelial cells. We will determine if antibodies that block adherence of P. yoelii infected reticulocytes to vascular endothelium in vitro also block localization of parasites to erythropoietic tissues in vivo and enhance the efficacy of MSP-based vaccines. These studies are built on the success of the malaria genome sequencing efforts, the ability to monitor the concurrent expression of large multigene families by microarray analysis, and the utilization of well-defined rodent models to conduct in vivo studies. Relevance: P. vivax causes 70-80 million cases of malaria each year. Efforts to develop vaccines to reduce P. vivax malaria are critical but must consider the unique aspects of the growth of this parasite in vivo. The proposed studies will increase our understanding of the factors that favor parasite invasion of subpopulations of erythrocytes in vivo to improve the design of vaccines that effectively inhibit the process.

描述（由申请人提供）：考虑到裂殖子（MSP）表面表达的抗原在红细胞侵袭和血清抗体可及性方面的功能重要性，人们的注意力集中在针对裂殖子（MSP）表面表达的抗原的血期疟疾疫苗的开发和测试上。这些努力以恶性疟原虫的体外研究和啮齿动物疟疾寄生虫的体内研究为指导，这些研究证明了抗体介导的对裂殖子侵入成熟红细胞的抑制作用。然而，约氏疟原虫的研究数据表明，在体内，这些相同的抗体不足以阻止裂殖子侵入网织红细胞。这似乎不仅仅是由于不同裂殖子蛋白参与的宿主红细胞上的受体存在差异。如果基于 MSP 的疫苗要有效对抗间日疟原虫（一种网织红细胞限制性疟原虫），就必须解决这个问题。我们的假设是，感染网织红细胞限制性疟原虫的红细胞定位于体内红细胞生成位点，成熟并将裂殖子释放到有利于与新形成的网织红细胞相互作用并减少裂殖子中和抗体暴露的环境中。为了检验这一假设，我们将用约氏疟原虫血期寄生虫进行体外和体内研究，这些寄生虫模仿人类疟疾寄生虫的限制性或非限制性宿主细胞偏好。我们将重点关注网织红细胞表面表达的疟原虫蛋白和变异表面抗原、它们在介导 pRBC 粘附到血管内皮中的作用以及它们在免疫逃避中的作用。具体来说，我们将定义在约氏疟原虫感染的网织红细胞中表达的疟原虫红细胞膜蛋白基因的子集，这些网织红细胞粘附在血管内皮细胞上，并监测其在免疫压力下寄生虫中表达的变化。我们将鉴定与血管内皮细胞表达的受体结合的表面暴露的约氏疟原虫网织红细胞膜蛋白。我们将确定在体外阻断约氏疟原虫感染的网织红细胞粘附到血管内皮的抗体是否也能在体内阻断寄生虫在红细胞生成组织中的定位并增强基于 MSP 的疫苗的功效。这些研究建立在疟疾基因组测序工作的成功、通过微阵列分析监测大型多基因家族同时表达的能力以及利用明确的啮齿动物模型进行体内研究的基础上。相关性：间日疟原虫每年导致 70-8000 万例疟疾病例。努力开发疫苗来减少间日疟原虫疟疾至关重要，但必须考虑这种寄生虫在体内生长的独特方面。拟议的研究将增加我们对有利于寄生虫侵入体内红细胞亚群的因素的理解，以改进有效抑制该过程的疫苗设计。