The primary long-term objective of this proposed research is to provide basic fundamental molecular biological and immunobiological information that will aid in the development of a blood stage merozoite vaccine against Plasmodium vivax, one of the two most prevalent species of human malaria. Although the parasite under investigation is P. vivax, the results of the proposed research will also have relevance towards increasing the understanding of the biology of P. falciparum merozoites, the other major species of human malaria. The proposed investigations will continue our characterizations of several P. vivax merozoite proteins and the genes encoding them that 1) have directly or indirectly an apparent function in the receptor mediated processes of merozoite invasion of erythrocytes, and 2) are likely to have a role in affecting the immunobiological relationship between P. vivax and humans by stimulating anti-P. vivax immune responses. Specifically, the proteins under study are organized internally or externally at the invasive apical pole of the merozoite or comprise elements of the organized surface coat of merozoites. Three of these proteins bind to erythrocytes in a manner consistent with receptor-like specificity and parasite biology and, therefore, likely have a direct role in the initial molecular events of merozoite invasion. The structure and binding domains of these proteins will be determined through immunochemical, molecular biological, and recombinant expression technologies in order to more effectively assess biological function and immunogenicity. The molecular and biological characterization of a fourth apically located protein could provide further insights into the role(s) of the poorly characterized merozoite apical microneme organelles and their contents in invasion. Three other proteins are members of a newly discovered family of merozoite coat proteins that are immunogens but also may play a paradoxical role in host-parasite biology by stimulating a naturally acquired immune mechanism that limits asexual blood stage parasitemias, while, concurrently, they may also have a role in promoting chronicity. The research is aimed at investigating aspects of the genetics and diversity of the family members and how this may affect the immune response mechanisms induced by these proteins and vice versa. The coordinated use of in-vitro merozoite invasion and attachment assays, immuno-electron microscopy, defined antibody and recombinant DNA reagents that have already been or will be developed, and the ability to use the simian malaria model, P. knowlesi, in addition to P. vivax, will aid in the more precise determination and clarification of the location(s), function, structure and possible interactive relationships of the merozoite proteins under investigation and further the rational development of potential vaccine candidates.
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