Avirulent strains of Salmonella typhimurium endowed with the ability to express cloned genes from other pathogens are being widely considered as platforms for the construction of polyvalent vaccines. Although Salmonella typhimurium are excellent carriers to stimulate mucosal and humoral immune responses directed to the heterologous antigens delivered by avirulent vaccine strains, the class I restricted immune responses against these antigens are generally poor. This limitation stems from the fact that Salmonella spp. remain inside the phagocytic vesicle throughout their entire intracellular stage. We have recently developed a system that overcomes this limitation. This system is based on the use the Salmonella type III secretion system to deliver effector bacterial proteins into the cytosol of infected cells. We have adapted this system to deliver heterologous viral epitopes into class I-antigen presenting to stimulate strong class I-restricted immune responses. It is the objective of our proposed research project to further develop the type III secretion-based delivery system into a versatile platform capable of delivery complex antigens to different compartments of the antigen-presenting cellular machinery. More specifically we propose: 1) To examine the size and/or structural limitations for the delivery of antigens by the S. typhimurium type III secretion system; 2) To evaluate the ability of the chimeric proteins constructed in specific Aim 1 to induce class I restricted immune responses after delivery by the type III secretion of avirulent vaccine strains of S. typhimurium.; 3) To adapt the S. typhimurium type III secretion system for the delivery of epitopes to the class II antigen presenting pathway; and 4) To evaluate the effect of mutations on S. typhimurium effector signaling proteins (e. g. SopE, SptP, SipA and SopB) on its ability to stimulate class I or class II restricted immune responses in vivo and in vitro. The studies proposed here will expand the use of the S. typhimurium type III secretion system to deliver complex antigens to both the class I and class II antigen presenting pathways. This will significantly broaden the utility of avirulent strains of Salmonella as platforms for the development of polyvalent vaccines.
|Platt, Andrew M; Rutkowski, Joseph M; Martel, Catherine et al. (2013) Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia. J Immunol 190:4608-20|
|Chen, Li-Mei; Briones, Gabriel; Donis, Ruben O et al. (2006) Optimization of the delivery of heterologous proteins by the Salmonella enterica serovar Typhimurium type III secretion system for vaccine development. Infect Immun 74:5826-33|
|Evans, David T; Chen, Li-Mei; Gillis, Jacqueline et al. (2003) Mucosal priming of simian immunodeficiency virus-specific cytotoxic T-lymphocyte responses in rhesus macaques by the Salmonella type III secretion antigen delivery system. J Virol 77:2400-9|
|Galan, J E (2001) Salmonella interactions with host cells: type III secretion at work. Annu Rev Cell Dev Biol 17:53-86|