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Infection and Immunity, February 2006, p. 1130-1140, Vol. 74, No. 2
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.2.1130-1140.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Role of Gluconeogenesis and the Tricarboxylic Acid Cycle in the Virulence of Salmonella enterica Serovar Typhimurium in BALB/c Mice

Merlin Tchawa Yimga,1,{dagger} Mary P. Leatham,1 James H. Allen,1,{ddagger} David C. Laux,1 Tyrrell Conway,2 and Paul S. Cohen1*

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 23 August 2005/ Returned for modification 29 September 2005/ Accepted 14 November 2005

In Salmonella enterica serovar Typhimurium, the Cra protein (catabolite repressor/activator) regulates utilization of gluconeogenic carbon sources by activating transcription of genes in the gluconeogenic pathway, the glyoxylate bypass, the tricarboxylic acid (TCA) cycle, and electron transport and repressing genes encoding glycolytic enzymes. A serovar Typhimurium SR-11 {Delta}cra mutant was recently reported to be avirulent in BALB/c mice via the peroral route, suggesting that gluconeogenesis may be required for virulence. In the present study, specific SR-11 genes in the gluconeogenic pathway were deleted (fbp, glpX, ppsA, and pckA), and the mutants were tested for virulence in BALB/c mice. The data show that SR-11 does not require gluconeogenesis to retain full virulence and suggest that as yet unidentified sugars are utilized by SR-11 for growth during infection of BALB/c mice. The data also suggest that the TCA cycle operates as a full cycle, i.e., a sucCD mutant, which prevents the conversion of succinyl coenzyme A to succinate, and an {Delta}sdhCDA mutant, which blocks the conversion of succinate to fumarate, were both attenuated, whereas both an SR-11 {Delta}aspA mutant and an SR-11 {Delta}frdABC mutant, deficient in the ability to run the reductive branch of the TCA cycle, were fully virulent. Moreover, although it appears that SR-11 replenishes TCA cycle intermediates from substrates present in mouse tissues, fatty acid degradation and the glyoxylate bypass are not required, since an SR-11 {Delta}fadD mutant and an SR-11 {Delta}aceA mutant were both fully virulent.

* Corresponding author. Mailing address: Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881. Phone: (401) 874-5920. Fax: (401) 874-2202. E-mail: pco1697u{at}postoffice.uri.edu.

Editor: J. B. Bliska

{dagger} Present address: Animal Disease Diagnostic Laboratory, Purdue University, West Lafayette, IN 47907.

{ddagger} Present address: inGenious Targeting Laboratory, Inc., Stony Brook, NY 11790.

Infection and Immunity, February 2006, p. 1130-1140, Vol. 74, No. 2
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.2.1130-1140.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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