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Infection and Immunity, March 2008, p. 1128-1134, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.01226-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Salmonella enterica Serovar Typhimurium Succinate Dehydrogenase/Fumarate Reductase Double Mutant Is Avirulent and Immunogenic in BALB/c Mice

Regino Mercado-Lubo,¹ Eric J. Gauger,^1, Mary P. Leatham,¹ Tyrrell Conway,² and Paul S. Cohen^1*

Department of Cell and Molecular Biology, University of Rhode Island, Kingston, Rhode Island 02881,¹ Department of Botany and Microbiology, University of Oklahoma, Norman, Oklahoma 73019²

Received 5 September 2007/ Returned for modification 10 October 2007/ Accepted 7 December 2007

Previously we showed that the tricarboxylic acid (TCA) cycle operates as a full cycle during Salmonella enterica serovar Typhimurium SR-11 peroral infection of BALB/c mice (M. Tchawa Yimga et al., Infect. Immun. 74:1130-1140, 2006). The evidence was that a sucCD mutant (succinyl coenzyme A [succinyl-CoA] synthetase), which prevents the conversion of succinyl-CoA to succinate, and a sdhCDA mutant (succinate dehydrogenase), which blocks the conversion of succinate to fumarate, were both attenuated, whereas an SR-11 aspA mutant (aspartase) and an SR-11 frdABCD mutant (fumarate reductase), deficient in the ability to run the reductive branch of the TCA cycle, were fully virulent. In the present study, evidence is presented that a serovar Typhimurium SR-11 frdABCD sdhCDA double mutant is avirulent in BALB/c mice and protective against subsequent infection with the virulent serovar Typhimurium SR-11 wild-type strain via the peroral route and is highly attenuated via the intraperitoneal route. These results suggest that fumarate reductase, which normally runs in the reductive pathway in the opposite direction of succinate dehydrogenase, can replace it during infection by running in the same direction as succinate dehydrogenase in order to run a full TCA cycle in an SR-11 sdhCDA mutant. The data also suggest that the conversion of succinate to fumarate plays a key role in serovar Typhimurium virulence. Moreover, the data raise the possibility that S. enterica frdABCD sdhCDA double mutants and frdABCD sdhCDA double mutants of other intracellular bacterial pathogens with complete TCA cycles may prove to be effective live vaccine strains for animals and humans.

Published ahead of print on 17 December 2007.

Editor: B. A. McCormick

Present address: Intervet Inc., P.O. Box 318, Millsboro, DE 19966.