The Tricarboxylic Acid (TCA) cycle is a key hub in metabolism, being responsible for generating NADH to be used as the primary electron donor for the respiratory electron transport chain (ETC). It is also provides metabolic intermediates for the rest of the cell; for example alpha-ketoglutarate is converted to the amino acid glutamate through the action of glutamate dehydrogenase.
A recent study from The Institute of Food Research in Norwich highlights the impact the TCA cycle on Salmonella Typhimurium infections. The researchers generated mutant strains of Salmonella in which various different enzymes in the TCA cycle were deleted. They then tested the ability of these bacterial strains to infect macrophages*. Deletion of 2-ketoglutarate dehydrogenase (sucAB), succinyl-CoA synthetase (sucCD) or succinate dehydrogenase (sdhCDAB) resulted in significantly increased bacterial accumulation in the macrophages (see graph, slightly edited from the original paper).
The authors of the study suggest that the difference in accumulation is due to a difference in ability to withstand macrophage anti-microbial defences. These involve the production of Reactive Oxygen Species (ROS; e.g. H2O2), which are known to damage the respiratory ETC. The authors suggest that a compromised TCA cycle will result in less NADH being produced, and therefore reduced flux through the ETC, so less ROS-induced damage will occur. This model isn’t directly tested within their experiments, but might explain their results.
However, when the researchers did the equivalent experiment in epithelial cells (which don’t have an ROS based defence mechanism) the mutant strains had a 30% decrease in their level of replication compared to the wildtypes. The Succinyl-CoA synthetase (sucCD) and α-ketoglutarate dehydrogenase (sucAB) mutants were also less able to infect mice. The results are therefore somewhat contradictory, but show that the primary metabolism of the pathogen is an important factor in infection.
*White blood cells that engulf pathogens and cells undergoing apoptosis as part of the immune response
Reference: Bowden SD, Ramachandran VK, Knudsen GM, Hinton JCD, Thompson A (2010) An Incomplete TCA Cycle Increases Survival of Salmonella Typhimurium during Infection of Resting and Activated Murine Macrophages. PLoS ONE 5(11): e13871. doi:10.1371/journal.pone.0013871