title: Live attenuated Salmonella vaccines against Mycobacterium tuberculosis with antigen delivery via the type III secretion system.
abstract: Tuberculosis remains a global health threat, and there is dire need to develop a vaccine that is safe and efficacious and confers long-lasting protection. In this study, we constructed recombinant attenuated Salmonella vaccine (RASV) strains with plasmids expressing fusion proteins consisting of the 80 amino-terminal amino acids of the type 3 secretion system effector SopE of Salmonella and the Mycobacterium tuberculosis antigens early secreted antigenic target 6-kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10). We demonstrated that the SopE-mycobacterial antigen fusion proteins were translocated into the cytoplasm of INT-407 cells in cell culture assays. Oral immunization of mice with RASV strains synthesizing SopE-ESAT-6-CFP-10 fusion proteins resulted in significant protection of the mice against aerosol challenge with M. tuberculosis H37Rv that was similar to the protection afforded by immunization with Mycobacterium bovis bacillus Calmette-Guérin (BCG) administered subcutaneously. In addition, oral immunization with the RASV strains specifying these mycobacterial antigens elicited production of significant antibody titers to ESAT-6 and production of ESAT-6- or CFP-10-specific gamma interferon (IFN-γ)-secreting and tumor necrosis factor alpha (TNF-α)-secreting splenocytes.
authors.affiliation: Center for Infectious Diseases and Vaccinology at Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Juárez-Rodríguez
authors.forename: Lourdes T
authors.initials: LT
authors.lastname: Arteaga-Cortés
authors.forename: Rebin
authors.initials: R
authors.lastname: Kader
authors.forename: Roy
authors.initials: R
authors.lastname: Curtiss
authors.forename: Josephine E
authors.initials: JE
authors.lastname: Clark-Curtiss
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins / Q000276:immunology; D022562:Salmonella Vaccines / Q000008:administration & dosage / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D007074:Immunoglobulin G; C557704:PTD4-apoptin protein; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D022562:Salmonella Vaccines; D032581:Tuberculosis Vaccines