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Infection and Immunity, April 2009, p. 1397-1405, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.01335-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Salmonella enterica Serovar Typhimurium Mutants Unable To Convert Malate to Pyruvate and Oxaloacetate Are Avirulent and Immunogenic in BALB/c Mice{triangledown}

Regino Mercado-Lubo,1 Mary P. Leatham,1 Tyrrell Conway,2 and Paul S. Cohen1*

Department of Cell and Molecular Biology, University of Rhode Island, Kingston, Rhode Island 028811,1 Department of Botany and Microbiology, University of Oklahoma, Norman, Oklahoma 7301922

Received 31 October 2008/ Returned for modification 9 December 2008/ Accepted 11 January 2009

Previously, we showed that the Salmonella enterica serovar Typhimurium SR-11 tricarboxylic acid (TCA) cycle must operate as a complete cycle for full virulence after oral infection of BALB/c mice (M. Tchawa Yimga, M. P. Leatham, J. H. Allen, D. C. Laux, T. Conway, and P. S. Cohen, Infect. Immun. 74:1130-1140, 2006). In the same study, we showed that for full virulence, malate must be converted to both oxaloacetate and pyruvate. Moreover, it was recently demonstrated that blocking conversion of succinyl-coenzyme A to succinate attenuates serovar Typhimurium SR-11 but does not make it avirulent; however, blocking conversion of succinate to fumarate renders it completely avirulent and protective against subsequent oral infection with the virulent serovar Typhimurium SR-11 wild-type strain (R. Mercado-Lubo, E. J. Gauger, M. P. Leatham, T. Conway, and P. S. Cohen, Infect. Immun. 76:1128-1134, 2008). Furthermore, the ability to convert succinate to fumarate appeared to be required only after serovar Typhimurium SR-11 became systemic. In the present study, evidence is presented that serovar Typhimurium SR-11 mutants that cannot convert fumarate to malate or that cannot convert malate to both oxaloacetate and pyruvate are also avirulent and protective in BALB/c mice. These results suggest that in BALB/c mice, the malate that is removed from the TCA cycle in serovar Typhimurium SR-11 for conversion to pyruvate must be replenished by succinate or one of its precursors, e.g., arginine or ornithine, which might be available in mouse phagocytes.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 028811. Phone: (401) 874-5920. Fax: (401) 874-2202. E-mail: pco1697u{at}postoffice.uri.edu

{triangledown} Published ahead of print on 21 January 2009.

Editor: A. J. Bäumler

Infection and Immunity, April 2009, p. 1397-1405, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.01335-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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