IMMUNOLOGICAL STUDY OF THE CS LIGAND AND ITS LIVER CELL RECEPTOR

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Immunoprophylaxis based on the induction of neutralizing antibodies to inhibit the interaction of virus, bacteria or bacterial toxins, with the corresponding host cellular receptors, forms the basis of numerous vaccines in current use throughout the world. In Project 3, the CS protein ligand, and the amino acid sequences which flank this region, will be used as antigens in an effort to produce monoclonal antibodies that can inhibit the binding of sporozoites to liver cells. The rodent malaria model will be used to assay the immunogenicity of synthetic constructs containing the optimal CS ligand, or flanking sequences, in order to determine whether vaccines designed to inhibit parasite/host cell interactions can protect against sporozoite challenge in vivo. We will also screen immune sera to determine whether antibodies are induced in man, either by natural infection or sporozoite immunization, which can bind to peptides representing the region II-plus ligand of the P. falciparum CS protein, and whether affinity purified human antibodies of this specificity can inhibit sporozoite/hepatocyte interactions in vitro. Whether tolerance of the host, or immune evasion by the parasite, modulate the response to these non-repeat regions of the CS protein will also be examined, since these factors will determine vaccine efficacy. The reciprocal studies will focus on the generation of polyclonal and monoclonal antibodies that recognize the CS-binding heparan sulfate proteoglycan on the liver cell, in order to characterize this receptor at the molecular and cellular level.