RovA, regulation and virulence in the Yersinia

The yersiniae are Gram-negative bacteria that belong to the Enterobacteriaceae family. Yersinia enterocolitica, Y. pseudotuberculosis, and Y. pestis are the only primary human pathogens of this genus. Y. enterocolitica and Y. pseudotuberculosis are enteropathogenic bacteria that are found widely in the environment and are usually transmitted by ingestion of contaminated food or water. Y. pestis is the causative agent of bubonic and pneumonic plague and a primary pathogen of rodents. Plague is normally transmitted to human hosts through the bite of an infected flea. All three pathogenic species of Yersinia express RovA, a conserved transcriptional regulator. In Y. enterocolitica and Y. pseudotuberculosis, RovA has been shown to regulate expression of invasin, an outer membrane protein that mediates binding to host epithelial cells in the intestinal mucosa. Virulence analysis indicates that a rovA mutant is significantly more attenuated than either wild-type Y. enterocolitica or an inv mutant, suggesting RovA regulates other loci, some of which may be virulence determinants.;The objectives of this dissertation were to define the RovA regulon in Yersinia and identify novel RovA-regulated virulence loci. Using microarray technology, many RovA-regulated genes were identified in Y. enterocolitica and Y. pestis. Comparison of the RovA-regulons from these two related species has provided some insight into the regulatory mechanism of RovA and revealed surprising differences in regulation that may highlight the evolutionary divergence of the yersiniae. By developing an animal model of bubonic plague, a role for RovA in Y. pestis pathogenesis has been established. Among the most down-regulated genes in the rovA mutant was the ph 6 antigen locus. RovA was shown to be required for expression of this locus under the inducing conditions previously described of high temperature and low pH. Mutation of psaA results in a significant virulence defect in bubonic plague with only a slight defect in pneumonic plague. This attenuation closely mimics that observed with the rovA mutant, suggesting that a large portion of the virulence defect of the rovA mutant in Y. pestis may be attributed to loss of this critical virulence determinant.