The structure and thermodynamic properties of Y. pestis capsular Caf1 antigen were studied to explain the failure of this protein to induce the cellular immune response. During the assembling of the Caf1 capsule, the collapse of Caf1 hydrophobic core results in the formation of extremely stable Caf1 fibers. This increases resistance of the Caf1 antigen to processing in macrophages and thereby abolishes the cellular immune response. Destabilization of Caf1 by heating caused a shift toward presentation by mature MHC class II. These new breakthrough findings render bases to overcome the self-protection mechanisms of the plague disease and develop effective vaccines. The essence of our approach is to make selected point mutations which do not change the overall 3D structure of the antigen but decreases its resistance to proteolytic processing inside macrophages. This results in the increase of the efficacy of presentation of CD4 T cell epitopes of antigens by macrophages to T cells while specificity of the generated antibodies will not essentially change. We have preliminary proved this theory by using such artificially designed Caf1 monomers. We forecast that knowledge-based engineered antigens will be the basis of plague vaccines of next generation. We have available molecular tools ready to explore in more detail the theoretical basis of engineered Caf1 antigen in a short time. Next we will show the applicability of the theory by developing experimental generic anti-Salmonella vaccine composed of the conservative SefD and SafD putative invasion subunits common for the main virulent strains of Salmonella spp. We strongly believe that our approach is the cutting-edge innovation to combat against dangerous pathogens in general. According to the proposal Prof. Zaviyalov is invited to Finland for 2 years to lead a European team which will investigate the applications of the new approach.
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