Monday, April 28, 2025
4/28/2025
IMMUNE RESPONSE TO P. VIVAX IN DUFFY (-) HUMANS - 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.
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