The evolution of bacterial pathogens not only occurs through the gain or loss of protein-coding genes but also through changes in the mechanisms by which those protein-coding genes are regulated. These alterations may result in genetically related bacteria that are phenotypically quite distinct. Yersinia pestis, responsible for the devastating disease plague, and Yersinia pseudotuberculosis, the causative agent of the mild, self-limiting disease Yersiniosis, are excellent examples of this phenomenon. Although these two species are highly genetically similar and Y. pestis is considered to be a recently evolved clone of Y. pseudotuberculosis, the routes of transmission, clinical disease manifestations, and mortality rates caused by each are dramatically different. It is still unclear as to how these closely related species cause such phenotypically distinct diseases. In recent years, the regulation of gene expression at the post-transcriptional level by small, noncoding RNAs (sRNAs) has gained considerable attention. sRNAs base-pair with target mRNAs to alter translation rates and therefore affect protein abundance. By using deep sequencing technology, my laboratory recently determined the global repertoire of sRNAs (aka the sRNA-ome) expressed by both Y. pestis and Y. pseudotuberculosis. This analysis revealed that, while the majority of sRNA genes identified are conserved in both species, the Y. pestis genome encodes 5 sRNA genes that are absent from Y. pseudotuberculosis. As we have shown that at least one of these Y. pestis-specific sRNAs is required for full virulence during pneumonic plague, we hypothesize that changes in the sRNA-ome of Y. pestis during its evolution from Y. pseudotuberculosis contributed to its specific ability to cause the disease plague by changing the regulation of shared and/or distinct virulence determinants. We will use sRNA gene disruption combined with animal models of infection to manipulate the sRNA content of Y. pestis to test how each Y. pestis-specific sRNA may affect the severity and outcome of bubonic and pneumonic plague in animals and if so, the mechanisms by which these sRNAs contribute to virulence. These studies will provide a unique insight into the evolution of bacterial pathogens at the post-transcriptional level and should be broadly applicable to other closely related but phenotypically distinct species.
The disease plague is caused by one of the most deadly pathogens known to humankind and continues to pose a public health threat, both naturally and through the use of Yersinia pestis as a bioweapon. An understanding of the evolutionary processes by which Y. pestis evolved from its ancestor Yersinia pseudotuberculosis, therefore, will allow us to determine the factors required to cause plague and mechanisms by which those factors are uniquely regulated between the species. This project is designed to elucidate those mechanisms at a genetic level, and may have implications for understanding how other bacterial pathogens have evolved as well.
| Eddy, J L; Schroeder, J A; Zimbler, D L et al. (2016) Proteolysis of plasminogen activator inhibitor-1 by Yersinia pestis remodulates the host environment to promote virulence. J Thromb Haemost 14:1833-43 |
| Zimbler, Daniel L; Eddy, Justin L; Schroeder, Jay A et al. (2016) Inactivation of Peroxiredoxin 6 by the Pla Protease of Yersinia pestis. Infect Immun 84:365-74 |
| Zimbler, Daniel L; Schroeder, Jay A; Eddy, Justin L et al. (2015) Early emergence of Yersinia pestis as a severe respiratory pathogen. Nat Commun 6:7487 |
| Eddy, Justin L; Schroeder, Jay A; Zimbler, Daniel L et al. (2015) Impact of the Pla protease substrate ?2-antiplasmin on the progression of primary pneumonic plague. Infect Immun 83:4837-47 |
| Schiano, Chelsea A; Koo, Jovanka T; Schipma, Matthew J et al. (2014) Genome-wide analysis of small RNAs expressed by Yersinia pestis identifies a regulator of the Yop-Ysc type III secretion system. J Bacteriol 196:1659-70 |
