Heat shock-related stress proteins are a family of highly conserved proteins present in all prokaryotes and eukaryotes. Identification and cloning of genes for stress proteins in Plasmodium falciparum has suggested that stress responses might be important in the adaptation of parasite. Malaria parasites spend part of their life cycle in a poikilothermic insect vector and the remainder in a warm blooded vertebrate host. Various life cycle stages of the parasite in the vertebrate host are subjected to sudden changes in the temperature. Stress proteins are markedly induced in the sporozoites during intra-hepatic development and in the erythrocytic stages of the parasites subjected to febrile temperatures. Studies have also shown that these parasite proteins with unique as well as host-like regions, are targets of natural immune response (antibody and cell- mediated). To investigate immunobiological significance of malarial stress proteins it is proposed to obtain stress protein-specific T cell clones and study effects of stress proteins on the production of cytokines described as 'endogenous pyrogens'. Induction and subsequent processing of stress proteins in the intra-hepatic parasites might result in the expression of antigenic peptides in the context of MHC class I molecules thus stimulating cell-mediated cytotoxic T cell responses directed against exo-erythrocytic stages. Genes for malarial stress proteins will be sub-cloned in live vectors vaccinia virus and/or Salmonella to investigate cytotoxic T cell responses against intra-hepatic stages. Increased expression of these proteins in the erythrocytic stages might stimulate macrophages to produce multifunctional cytokines, i.e. tumor necrosis factor, interleukin-1, interleukin-6, and regulators of acute phase reaction. An effect of recombinant stress proteins on the production of cytokines by the activated macrophages will suggest a role for these antigens in the pathogenesis of acute malaria. The proposed investigations on the analysis of T cell epitopes in the stress proteins will lead to the identification of unique epitopes of potential immunological significance and possibly protective immunity.
