title: Salmonella enterica serovar typhimurium trxA mutants are protective against virulent challenge and induce less inflammation than the live-attenuated vaccine strain SL3261.
abstract: In Salmonella enterica serovar Typhimurium, trxA encodes thioredoxin 1, a small, soluble protein with disulfide reductase activity, which catalyzes thiol disulfide redox reactions in a variety of substrate proteins. Thioredoxins are involved as antioxidants in defense against oxidative stresses, such as exposure to hydrogen peroxide and hydroxyl radicals. We have made a defined, complete deletion of trxA in the mouse-virulent S. Typhimurium strain SL1344 (SL1344 trxA), replacing the gene with a kanamycin resistance gene cassette. SL1344 trxA was attenuated for virulence in BALB/c mice by the oral and intravenous routes and when used in immunization experiments provided protection against challenge with the virulent parent strain. SL1344 trxA induced less inflammation in murine spleens and livers than SL3261, the aroA mutant, live attenuated vaccine strain. The reduced splenomegaly observed following infection with SL1344 trxA was partially attributed to a reduction in the number of both CD4(+) and CD8(+) T cells and B lymphocytes in the spleen and reduced infiltration by CD11b(+) cells into the spleen compared with spleens from mice infected with SL3261. This less severe pathological response indicates that a trxA mutation might be used to reduce reactogenicity of live attenuated vaccine strains. We tested this by deleting trxA in SL3261. SL3261 trxA was also less inflammatory than SL3261 but was slightly less effective as a vaccine strain than either the SL3261 parent strain or SL1344 trxA.
authors.affiliation: Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, United Kingdom. sep34@cam.ac.uk
authors.forename: S E
authors.initials: SE
authors.lastname: Peters
authors.forename: G K
authors.initials: GK
authors.lastname: Paterson
authors.forename: E S D
authors.initials: ES
authors.lastname: Bandularatne
authors.forename: H C
authors.initials: HC
authors.lastname: Northen
authors.forename: S
authors.initials: S
authors.lastname: Pleasance
authors.forename: C
authors.initials: C
authors.lastname: Willers
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: A K
authors.initials: AK
authors.lastname: Foote
authors.forename: F
authors.initials: F
authors.lastname: Constantino-Casas
authors.forename: T J
authors.initials: TJ
authors.lastname: Scase
authors.forename: B A
authors.initials: BA
authors.lastname: Blacklaws
authors.forename: C E
authors.initials: CE
authors.lastname: Bryant
authors.forename: P
authors.initials: P
authors.lastname: Mastroeni
authors.forename: I G
authors.initials: IG
authors.lastname: Charles
authors.forename: D J
authors.initials: DJ
authors.lastname: Maskell
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced*; D007275:Injections, Intravenous; D008070:Lipopolysaccharides; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009154:Mutation; D012481:Salmonella Infections, Animal / Q000473:pathology / Q000517:prevention & control*; D022562:Salmonella Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000473:pathology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D022562:Salmonella Vaccines; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4