Enhanced immune responses to viral epitopes by combining macrophage-inducible expression with multimeric display on a Salmonella vector.
In this study, the immunogenicity of chimeric 987P fimbriae on a Salmonella vaccine strain was improved by optimizing fimbrial expression. The constitutive tetA promoter and the in vivo activated nirB and pagC promoters were evaluated for their use to express two epitopes of the transmissible gastroenteritis virus (TGEV) spike protein carried by fimbriae which were displayed on a Salmonella vaccine strain. Constructs with the pagC promoter were shown to drive increased expression of chimeric 987P fimbriae in macrophages as well as in Mg(2+)-poor media, mimicking a major environmental signal found in Salmonella-containing endocytic vacuoles of macrophages. Mice immunized orally with a Salmonella vaccine strain which expressed chimeric fimbriae from the pagC promoter elicited significantly higher mucosal and systemic immune responses to both the 987P fimbriae and the TGEV epitopes than mice immunized with the same strain hosting a tetA or nirB promoter-driven expression plasmid. Moreover, only the Salmonella vaccine strains harboring a plasmid with the pagC promoter, with or without an additional tetA promoter in tandem, elicited neutralizing antibodies to TGEV. This indicated that the pagC promoter can be used successfully to improve epitope-display by chimeric fimbriae on Salmonella vaccine strains for the induction of a desired immune response.
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104-6049, USA.
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Schifferli
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D002460:Cell Line; D000939:Epitopes; D029968:Escherichia coli Proteins; D005260:Female; D010861:Fimbriae, Bacterial / Q000276:immunology*; D005822:Genetic Vectors; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D007422:Intestines / Q000276:immunology; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D009572:Nitrite Reductases; D011401:Promoter Regions, Genetic; D012486:Salmonella typhimurium / Q000235:genetics* / Q000276:immunology; D005760:Transmissible gastroenteritis virus / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*
D001426:Bacterial Proteins; D000939:Epitopes; D029968:Escherichia coli Proteins; D007074:Immunoglobulin G; D008565:Membrane Proteins; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; C066766:pagC protein, Salmonella typhimurium; D009572:Nitrite Reductases; C079730:NirB protein, E coli