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Background  In comparison to the comprehensive analyses performed on virulence gene expression, regulation and action, the intracellular metabolism of  Salmonella  during infection is a relatively under-studied area. We investigated the role of the tricarboxylic acid (TCA) cycle in the intracellular replication of  Salmonella  Typhimurium in resting and activated macrophages, epithelial cells, and during infection of mice.    Methodology/Principal Findings  We constructed deletion mutations of 5 TCA cycle genes in  S . Typhimurium including  gltA, mdh ,  sdhCDAB, sucAB , and  sucCD.  We found that the mutants exhibited increased net intracellular replication in resting and activated murine macrophages compared to the wild-type. In contrast, an epithelial cell infection model showed that the  S . Typhimurium Δ sucCD  and Δ gltA  strains had reduced net intracellular replication compared to the wild-type. The glyoxylate shunt was not responsible for the net increased replication of the TCA cycle mutants within resting macrophages. We also confirmed that, in a murine infection model, the  S . Typhimurium Δ sucAB  and Δ sucCD  strains are attenuated for virulence.    Conclusions/Significance  Our results suggest that disruption of the TCA cycle increases the ability of  S . Typhimurium to survive within resting and activated murine macrophages. In contrast, epithelial cells are non-phagocytic cells and unlike macrophages cannot mount an oxidative and nitrosative defence response against pathogens; our results show that in HeLa cells the  S . Typhimurium TCA cycle mutant strains show reduced or no change in intracellular levels compared to the wild-type  [1] . The attenuation of the  S . Typhimurium Δ sucAB  and Δ sucCD  mutants in mice, compared to their increased net intracellular replication in resting and activated macrophages suggest that  Salmonella  may encounter environments within the host where a complete TCA cycle is advantageous.

An Incomplete TCA Cycle Increases Survival of Salmonella Typhimurium during Infection of Resting and Activated Murine Macrophages