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: 8105881
• 负责人: RUOBING WANG
• 金额: $ 33.89万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105881
• 关键词: Antibodies; Antibody Formation; Antigen Receptors; Antigen Targeting; Antigens; Area; Autologous; B-Lymphocytes; Binding Proteins; Biological; Biological Assay; Blood; Cells; Chloroquine; Clinical; Cloning; Code; Collaborations; Colombia; Complementary DNA; Country; Culicidae; Data; Dendritic Cells; Detection; Development; Economic Development; Erythrocytes; Exhibits; Exons; Expressed Sequence Tags; Falciparum Malaria; Figs - dietary; Frequencies; Genes; Genomics; Grant; Human; Immune; Immune Sera; Immune response; Immunofluorescence Immunologic; In Vitro; Individual; Infection; Knowledge; Lead; Length; Leukapheresis; Life; Link; Liver; Lymphocyte; Malaria; Malaria Vaccines; Medicine; Membrane Proteins; Merozoite Surface Protein 1; Messenger RNA; Minor; Modeling; Molecular Profiling; Mus; National Institute of Allergy and Infectious Disease; Organism; Parasites; Participant; Pattern; Peptide Signal Sequences; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasmids; Plasmodium falciparum; Plasmodium vivax; Population; Primates; Principal Investigator; Process; Prophylactic treatment; Proteins; Proteomics; Recruitment Activity; Refractory; Research; Research Personnel; Resistance; Reticulocytes; Reverse Transcriptase Polymerase Chain Reaction; Screening procedure; Serum; Shotguns; Signal Transduction; Site; Specificity; Spleen; Sporozoite vaccine; Sporozoites; Staging; Standardization; Surface; System; T cell response; T-Lymphocyte; Testing; Translational Research; Transmembrane Domain; Vaccines; Venipunctures; Vivax Malaria; Waxes; apical membrane; base; chemokine; circumsporozoite protein; comparative; design; drug testing; enzyme linked immunospot assay; experience; expression vector; genome sequencing; immunogenic; immunogenicity; in vivo; laser capture microdissection; monocyte; novel; pesticide resistance; prevent; programs; relational database; response; vaccine development; vector; volunteer

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（由申请人提供）：每年300-5亿例疟疾病例中至少有20％是由疟原虫体内感染引起的。尽管疟原虫疟疾很少致死，但它会引起大量的人类苦难，并抑制许多疟疾流行国家的经济发展。与最致命的人类疟疾寄生虫P. falciparum相比，维瓦克斯的研究相对较少，主要是因为它不能在体外培养。因此，与恶性疟原虫相比，在Vivax疫苗的发育中取得的进展要少得多。在网状细胞表面上，侵袭了假子蛋白酶在网状细胞中的趋化因子（DARC）的表达取决于趋化因子（DARC）的表达。缺乏DARC [F（Y-）J的个体完全抵抗了Vivax血液阶段的感染，但应容易受到因孢子虫的侵袭而引发的肝脏阶段感染。此外，肝阶段寄生虫应在FY（ - ）个体中正常发育，但是从肝脏中释放的梅罗寄生虫不会期望引发血液阶段感染。因此，暴露于感染的蚊子的菲瓦克斯流行区域中的FY（ - ）个体应主要对肝阶段抗原表现出免疫反应，而FY（+）个体应同时对肝脏和血液阶段抗原反应，并具有针对血液级抗原的主要反应。应该在此处提出的新的分析中使用来自FY（ - ）个体的淋巴细胞来识别肉毒杆菌前P. vivax抗原 是细胞免疫反应的靶标。淋巴细胞和血清将从居住在哥伦比亚省Vivax Plecomead地区的FY（+）和FY（ - ）个体中收集。新型ELISPOT测定法，如果将用于表征对1000种从维瓦克斯基因组序列鉴定出的新型蛋白质的免疫反应。将在小鼠中进行免疫原性研究，以确认通过人体免疫细胞的体外筛查过程鉴定的抗原蛋白在体内具有免疫原性，并为亚细胞定位生成抗血清，以确认新型抗原的阶段特异性。