Depletion of Glucose Activates Catabolite Repression during Pneumonic Plague.

Bacterial pathogenesis depends on changes in metabolic and virulence gene expression in response to changes within a pathogen's environment. The plague-causing pathogen, , requires expression of the gene encoding the Pla protease for progression of pneumonic plague. The catabolite repressor protein Crp, a global transcriptional regulator, may serve as the activator of in response to changes within the lungs as disease progresses. By using gene reporter fusions, the spatial and temporal activation of the and promoters was measured in a mouse model of pneumonic plague. In the lungs, was highly expressed in bacteria found within large aggregates resembling biofilms, while expression increased over time independent of the aggregated state. Increased expression of and correlated with a reduction in lung glucose levels. Deletion of the glucose-specific phosphotransferase system EIIBC (PtsG) of rescued glucose levels in the lungs, resulting in reduced expression of both and We propose that activation of expression during pneumonic plague is driven by an increase of both Crp and cAMP levels following consumption of available glucose in the lungs by Thus, Crp operates as a sensor linking the nutritional environment of the host to regulation of virulence gene expression. Using as a model for pneumonia, we discovered that glucose is rapidly consumed, leading to a catabolite-repressive environment in the lungs. As a result, expression of the gene encoding the plasminogen activator protease, a target of the catabolite repressor protein required for pathogenesis, is activated. Interestingly, expression of the catabolite repressor protein itself was also increased in the absence of glucose but only in biofilms. The data presented here demonstrate how a bacterial pathogen senses changes within its environment to coordinate metabolism and virulence gene expression.