pckA-deficient Mycobacterium bovis BCG shows attenuated virulence in mice and in macrophages

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Abstract
Phosphoenolpyruvate carboxykinase (PEPCK) catalyses the reversible decarboxylation and phosphorylation of oxaloacetate (OAA) to form phosphoenolpyruvate (PEP). In this study, the regulation of the PEPCK-encoding genepckAwas examined through the evaluation of green fluorescent protein expression driven by thepckApromoter. The results showed thatpckAwas upregulated by acetate or palmitate but downregulated by glucose. Deletion of thepckAgene ofMycobacteriumbovisBCG led to a reduction in the capacity of the bacteria to infect and survive in macrophages. Moreover, mice infected with ΔpckABCG were able to reduce the bacterial load much more effectively than mice infected with the parental wild-type bacteria. This attenuated virulence was reflected in the degree of pathology, where granuloma formation was diminished both in numbers and degree. The data indicate that PEPCK activity is important during establishment of infection. Whether its role is in the gluconeogenic pathway for carbohydrate formation or in the conversion of PEP to OAA to maintain the TCA cycle remains to be determined.