title: Salmonella typhi and S typhimurium derivatives harbouring deletions in aromatic biosynthesis and Salmonella Pathogenicity Island-2 (SPI-2) genes as vaccines and vectors.
abstract: The S. typhimurium strain (TML deltaaroC deltassaV) WT05, harbouring defined deletions in genes involved in both the aromatic biosynthesis pathway (aroC) and the Salmonella Pathogenicity Island-2 (SPI-2) (ssaV) was shown to be significantly attenuated in C57 BL/6 interferon gamma knockout mice following oral inoculation. Similarly, the S. typhi strain (Ty2 deltaaroC deltassaV) ZH9 harbouring the aroC and ssaV mutations propagated less efficiently than wild type in human macrophages. These studies demonstrated the attractive safety profile of the aroC ssaV mutant combination. Strains S. typhimurium (TML deltaaroC deltassaV ) WT05 and S. typhi (Ty2 deltaaroC deltassaV) ZH9 were subsequently tested as vaccine vectors to deliver E. coli heat-labile toxin (LT-B) mucosally to mice. Mice inoculated orally with S. typhimurium (TML deltaaroC deltassaV) WT05 expressing LT-B (WT05/LT-B) elicited high titres of both LT-specific serum IgG and intestinal IgA, although no specific IgA was detected in the vagina. Similarly, intranasal inoculation of mice with S. typhi (Ty2 deltaaroC deltassaV) ZH9 expressing LT-B (ZH9/LT-B) elicited even higher titres of LT-specific serum antibody as well as LT-specific Ig in the vagina. We conclude that deltaaroC deltassaV strains of Salmonella are highly attenuated and are promising candidates both as human typhoid vaccines and as vaccine vectors for the delivery of heterologous antigens.
authors.affiliation: Microscience Limited, 545 Eskdale Road, Winnersh Triangle, Wokingham, Berkshire RG41 5TU, UK. s.khan@microscience.com
authors.forename: Shahid A
authors.initials: SA
authors.lastname: Khan
authors.forename: Richard
authors.initials: R
authors.lastname: Stratford
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Nicola
authors.initials: N
authors.lastname: Mckelvie
authors.forename: Trevor
authors.initials: T
authors.lastname: Bellaby
authors.forename: Zoe
authors.initials: Z
authors.lastname: Hindle
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Sinha
authors.forename: Shayne
authors.initials: S
authors.lastname: Eltze
authors.forename: Piero
authors.initials: P
authors.lastname: Mastroeni
authors.forename: Derek
authors.initials: D
authors.lastname: Pickard
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.forename: Steven N
authors.initials: SN
authors.lastname: Chatfield
authors.forename: Frank R
authors.initials: FR
authors.lastname: Brennan
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D001427:Bacterial Toxins / Q000096:biosynthesis / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology*; D002470:Cell Survival; D004768:Enterotoxins / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D029968:Escherichia coli Proteins; D005260:Female; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000378:metabolism*; D018928:Immunity, Mucosal / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D007422:Intestines / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D012485:Salmonella typhi / Q000235:genetics* / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics* / Q000276:immunology*; D014621:Vagina / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D006841:Hydrocarbons, Aromatic; D007074:Immunoglobulin G; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella; D007371:Interferon-gamma; C027538:heat-labile enterotoxin, E coli