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Infection and Immunity, September 2006, p. 5140-5151, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00449-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Thioredoxin 1 Promotes Intracellular Replication and Virulence of Salmonella enterica Serovar Typhimurium

Eva Bjur,1*,{dagger} Sofia Eriksson-Ygberg,1,{dagger} Fredrik Åslund,2 and Mikael Rhen1

Microbiology and Tumor Biology Center, Karolinska Institutet, Nobels väg 16, 171 77 Stockholm, Sweden,1 European Patent Office, The Hague, The Netherlands2

Received 20 March 2006/ Returned for modification 26 April 2006/ Accepted 10 May 2006

The effect of the cytoplasmic reductase and protein chaperone thioredoxin 1 on the virulence of Salmonella enterica serovar Typhimurium was evaluated by deleting the trxA, trxB, or trxC gene of the cellular thioredoxin system, the grxA or gshA gene of the glutathione/glutaredoxin system, or the dsbC gene coding for a thioredoxin-dependent periplasmic disulfide bond isomerase. Mutants were tested for tolerance to oxidative and nitric oxide donor substances in vitro, for invasion and intracellular replication in cultured epithelial and macrophage-like cells, and for virulence in BALB/c mice. In these experiments only the gshA mutant, which was defective in glutathione synthesis, exhibited sensitization to oxidative stress in vitro and a small decrease in virulence. In contrast, the trxA mutant did not exhibit any growth defects or decreased tolerance to oxidative or nitric oxide stress in vitro, yet there were pronounced decreases in intracellular replication and mouse virulence. Complementation analyses using defined catalytic variants of thioredoxin 1 showed that there is a direct correlation between the redox potential of thioredoxin 1 and restoration of intracellular replication of the trxA mutant. Attenuation of mouse virulence that was caused by a deficiency in thioredoxin 1 was restored by expression of wild-type thioredoxin 1 in trans but not by expression of a catalytically inactive variant. These results clearly imply that in S. enterica serovar Typhimurium, the redox-active protein thioredoxin 1 promotes virulence, whereas in vitro tolerance to oxidative stress depends on production of glutathione.

* Corresponding author. Mailing address: Microbiology and Tumor Biology Center, Karolinska Institutet, Nobels väg 16, 177 71 Stockholm, Sweden. Phone: 46-8-52486252. Fax: 46-8-330498. E-mail: Eva.Bjur{at}ki.se.

Editor: A. D. O'Brien

{dagger} E.B. and S.E.-Y. contributed equally to this work.

Infection and Immunity, September 2006, p. 5140-5151, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00449-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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