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

描述（由申请人提供）：每年3 -5亿疟疾病例中至少有20%是由间日疟原虫感染引起的。虽然间日疟很少致命，但它在许多疟疾流行国家造成了巨大的人类痛苦并阻碍了经济发展。与最致命的人类疟疾寄生虫恶性疟原虫相比，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小得多。间日疟原虫分裂子侵入网织红细胞取决于网织细胞表面达菲抗原/趋化因子受体（DARC）的表达。缺乏DARC [F(y-)J]的个体对间日疟原虫血期感染完全耐药，但对孢子虫入侵引发的肝期感染应敏感。此外，肝期寄生虫应该在Fy（-）个体中正常发育，但从肝脏释放的分裂子不会引发血期感染。因此，居住在间日疟原虫流行地区暴露于受感染蚊子的Fy（-）个体应主要对肝期抗原产生免疫应答，而Fy（+）个体应同时对肝期和血期抗原产生免疫应答，并以血期抗原为主。这应该是可能的使用淋巴细胞从Fy（-）个人在新的检测中提出，以确定前红血球期间日疟原虫抗原

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.