Identification of host-adapted metabolic functions important for Yersinia pseudotuberculosis virulence

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Initial colonization of the gut and subsequent penetration of the intestinal epithelial layer by the enteric pathogen Yersinia pseudotuberculosis demands expression of a special set of early-stage virulence genes, whereas persistence and multiplication in subepithelial tissues and organs requires synthesis of other pathogenicity factors, e.g. the antiphagocytic Yop proteins. A complex network of transcriptional and post-transcriptional regulatory systems was identified to control expression of these virulence factors and important metabolic functions. In particular, the central carbon metabolism (glycolysis, TCA cycle) and associated amino acid and nucleoside catabolism were found to be co-regulated with expression of Yersinia virulence functions in response to temperature and nutrient availability. To gain a deeper insight into the host-adapted metabolism of Yersinia, the full spectrum of metabolic changes in response to the different virulence associated conditions (changes of temperature, nutrients, oxygen availability) will be elucidated using metabolome, fluxome, transcriptional and 13C-isotopologue profiling techniques. Additionally the molecular mechanisms mediating fine-tuned coregulation of metabolic and virulence genes over the course of the infection will be elucidated. Subsequently, expression and role of the identified host-adapted virulence pathways for pathogenesis will be evaluated in an established mouse infection model. Gained knowledge about crucial host-adapted metabolic pathways of an extracellular fast growing intestinal pathogen may lead to the identification of new targets for novel anti-infective compounds.