Immune Response to P. vivax in Duffy (-) Humans

达菲 (-) 人类对间日疟原虫的免疫反应

• 批准号: 7179167
• 负责人: RUOBING WANG
• 金额: $ 29.55万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179167
• 关键词: Colombia; Plasmodium; T lymphocyte; antibody formation; antimicroorganism antibody; blood group antigens; circumsporozoite protein; clinical research; enzyme linked immunosorbent assay; functional /structural genomics; genetically modified animals; human subject; immunofluorescence technique; interferon gamma; laboratory mouse; leukocyte activation /transformation; life cycle; malaria; malaria vaccines; microorganism immunology; molecular biology information system; molecular cloning; protein signal sequence; protozoal antigen; transfection /expression vector; vaccine development

DESCRIPTION (provided by the applicant): At least 20% of the 300-500 million annual cases of malaria are caused by infection with Plasmodium vivax. Although P. vivax malaria is rarely lethal, it causes a great deal of human suffering and inhibits economic development in many malaria-endemic countries. P. vivax is relatively little studied compared to the most lethal human malaria parasite P. falciparum, primarily because it cannot be cultured in vitro. Consequently, far less progress has been achieved in P. vivax vaccine development compared to P. falciparum. Invasion of P. vivax merozoites into reticulocytes is dependent upon the expression of the Duffy antigen/receptor for chemokines (DARC) on the reticulocyte surface. Individuals lacking DARC [F(y-)J are completely resistant to infection by P. vivax blood stages, but should be susceptible to liver stage infections initiated by the invasion of sporozoites. Furthermore, liver stage parasites should develop normally in Fy(-) individuals, but the merozoites released from the liver would not be expected to initiate blood stage infections. Consequently, Fy(-) individuals residing in P. vivax endemic areas who are exposed to infected mosquitoes should exhibit immune responses primarily to liver stage antigens, whereas Fy(+) individuals should respond to both liver and blood stage antigens, with a predominant response directed to the blood stage antigens. It should be possible to use lymphocytes from Fy(-) individuals in novel assays proposed here to identify pre-erythrocytic stage P. vivax antigens that are targets of cellular immune responses. Lymphocytes and sera will be collected from Fy(+) and Fy(-) individuals living in P. vivax endemic areas in Columbia. Novel ELISPOT assays and IF As will be used to characterize the immune responses to 100 novel proteins identified from the P. vivax genome sequence. Immunogenicity studies will be conducted in mice to confirm that the antigenic proteins identified through the in vitro screening process in human immune cells are immunogenic in vivo, and to generate the antisera for subcellular localization to confirm the stage specificity of the novel antigens.

描述（由申请方提供）：每年3 - 5亿例疟疾病例中至少有20%是由间日疟原虫感染引起的。虽然间日疟原虫疟疾很少致命，但在许多疟疾流行的国家，它给人类造成了巨大的痛苦，并阻碍了经济发展。与最致命的人类恶性疟原虫相比，间日疟原虫的研究相对较少，主要是因为它不能在体外培养。因此，与恶性疟原虫相比，间日疟原虫疫苗开发取得的进展要少得多。间日疟原虫裂殖子侵入网织红细胞依赖于网织红细胞表面Duffy抗原/趋化因子受体（DARC）的表达。缺乏DARC [F（γ-）]的个体对间日疟原虫血液阶段的感染具有完全抗性，但应易受由子孢子入侵引发的肝脏阶段感染。此外，肝期寄生虫应在Fy（-）个体中正常发育，但从肝脏释放的裂殖子预计不会引发血液期感染。因此，居住在间日疟原虫流行区的暴露于受感染蚊子的Fy（-）个体应主要对肝脏阶段抗原表现出免疫应答，而Fy（+）个体应对肝脏和血液阶段抗原都有应答，其中主要应答针对血液阶段抗原。在本文提出的新的检测方法中，应该可以使用来自Fy（-）个体的淋巴细胞来鉴定红细胞前期间日疟原虫抗原 是细胞免疫反应的目标。将从生活在哥伦比亚间日疟原虫流行区的Fy（+）和Fy（-）个体中采集淋巴细胞和血清。新型ELISPOT测定和IFA将用于表征对从间日疟原虫基因组序列鉴定的100种新型蛋白质的免疫应答。将在小鼠中进行免疫原性研究，以确认通过人免疫细胞体外筛选过程鉴定的抗原蛋白在体内具有免疫原性，并生成用于亚细胞定位的抗血清，以确认新抗原的阶段特异性。