RovA regulon and virulence of Yersinia enterocolitica

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DESCRIPTION (provided by applicant): Yersinia enterocolitica is a bacterial pathogen responsible for a wide range of clinical syndromes but is primarily associated with gastrointestinal disorders. The enteropathogenic yersiniae have served as important models for the study of bacterial pathogenesis at the molecular level due in large part to their ease of manipulation in the laboratory, the existence of a sequenced genome, and the existence of an excellent murine model of infection. In recent years a number of important paradigms of pathogenesis have emerged from the studies of Y. enterocolitica and its companion enteropathogen, Y. pseudotuberculosis. Type Ill secretion systems (TTSS) were first described in these bacteria and the ysc TTSS of yersiniae remains one of the best characterized. In addition Y. enterocolitica and Y. pseudotuberculosis have served as important models of bacterial invasion, a process primarily encoded by the inv gene. In studies to further our knowledge of inv and its role in virulence we recently identified a gene, rovA, that regulates expression of inv both in the lab and during an infection. Virulence studies with a rovA mutant indicated that the rovA mutant was significantly less virulent than the wildtype strain or the inv mutant. Evidence suggests that RovA regulates previously undescribed virulence determinants. A more detailed examination of the rovA mutant with the host indicated it is defective in its ability to induce production of IL-1alpha and its ability to disseminate to deeper tissues. The inability to induce IL-1a appears to result in the inability of the host to trigger an inflammatory response in the Peyer's patches despite the presence of several other proinflammatory cytokines. Preliminary evidence also suggests that the failure to induce IL-1a is at least partly responsible for the avirulence of the rovA mutant. Based on these results and other information, we hypothesize that production of IL-1a locally in the Peyer's patches during infection is necessary for the full inflammatory response that in turn affects systemic dissemination and virulence of the bacteria. Therefore by studying aspects of the host-pathogen interaction revealed by analyzing the rovA mutant in vivo, and together with studying the RovA regulon, we can gain a better understanding of the molecular details of the early host-pathogen interactions that affect virulence. Specifically we propose: (1) Characterization of the IL-1a response in virulence and dissemination of Y. enterocolitica; (2) The role of RovA regulated genes in virulence, the IL-1a response and dissemination; (3) The mechanism of RovA regulation of gene expression.