The in vitro and in vivo regulation and expression of Yersinia enterocolitica type III secretion systems

The genus Yersinia contains three species that are pathogenic to humans; Y. pestis, the causative agent of the plague, Y. pseudotuberculosis, and Y. enterocolitica, which both cause a gastrointestinal disease. As pathogens, the primary goal of these species is to colonize their host. To accomplish this goal the bacteria need to avoid the host's innate immune response. Pathogenic Yersinia species along with many other Gram negative pathogens have acquired type III secretion (T3S) systems which they use to translocate toxic effector proteins from their cytosoplam to the cytosol of eukaryotic host cells. These effector proteins subvert the host immune response allowing the bacteria to colonize the host's tissues and cause disease. Y. enterocolitica biovar 1B encodes two T3S systems which are important to the virulence of the bacteria. The plasmid encoded Ysc T3S system is common to all pathogenic species of Yersinia and has been extensively studied as the paradigm of T3S. The chromosomally encoded Ysa T3S system is possessed by only a small number of Yersinia isolates including Y. enterocolitica biovar 1B. These studies analyze the mechanisms of regulation of both T3S systems. It was known that the Ysc T3S system is regulated primarily through the transcriptional activator VirF, which is regulated in a post-translational manner by the histone-like protein YmoA. In attempting to determine mechanisms of transcriptional regulation it was found that virF is transcribed as an operon with the upstream gene yscW, which encodes a lipoprotein that is part of the T3S injectisome. It was further determined that the global regulator CRP acts in an indirect manner to activate expression of virF through an undetermined intermediate. Expression of the Ysa T3S system is induced in vitro by growth at 26°C in a high salt media, conditions which would seem to preclude a role in a mammalian infection. These studies demonstrate that the Ysa T3S system is expressed in a contact-dependent manner during the infection of human epithelial cells. Additionally, using the mouse model of yersiniosis it was determined that the Ysa system is expressed throughout the course of an infection.