Yersinia pestis and Yersinia pseudotuberculosis are two bacterial pathogens that are very closely related, yet cause vastly different diseases in the mammalian host. Y. pestis is infamous for causing the devastating disease plague, while Y. pseudotuberculosis infection often results in a mild, self-limiting gastrointestinal illness. While genetically similar, the distinct mechanisms by which these two bacterial species interact with the host is of great interest to our group.
Shared amongst both pathogens is a protein called Hfq, which serves as a chaperone for small, non-coding regulatory RNAs (sRNAs). Much like microRNAs in eukaryotes, bacterial sRNAs act to post-transcriptionally regulate gene expression, affecting a large number of proteins that are involved in metabolism, stress response, and virulence. One set of projects in the lab centers on understanding the post-transcriptional regulatory networks controlled by Hfq and sRNAs in both Yersinia species, particularly as they relate to virulence. We anticipate that the similarities and differences we identify between Y. pestis and Y. pseudotuberculosis in this regard will provide keen insight into how a relatively mild pathogen evolved into one of the most deadly known to mankind.
We are also interested in determining the mechanisms by which Y. pestis specifically causes primary pneumonic plague, a respiratory form of disease that Y. pseudotuberculosis does not produce. We recently discovered that a Y. pestis-specific bacterial protein known as the plasminogen activator protease (Pla) is a critical virulence factor that allows Y. pestis to rapidly overwhelm the lungs and cause a fatal pneumonia. Thus, another set of projects in the lab focuses on dissecting the mechanisms by which Pla controls the development of pneumonic plague. These include understanding the interaction of Y. pestis and Pla with the mammalian fibrinolytic and coagulation cascades, the identification of additional host substrates cleaved by Pla that lead to the development of a severe pneumonia, and the means by which Y. pestis regulates Pla expression in the lungs that result in these phenomena.
These projects combine modern molecular, genetic, and biochemical techniques with tissue culture and animal models of infection to understand the interactions of Y. pestis and Y. pseudotuberculosis with the mammalian host. While certain strains of Y. pestis are avirulent and can be safely handled in a biosafety level (BSL)-2 lab, we will also be certified to work with fully virulent Y. pestis in a dedicated BSL-3 laboratory. Therefore, members of the lab will be trained in both the safety and security measures that are required for work on select agent pathogens such as Y. pestis.
Selected Publications:
Lathem, W. W., P. A. Price, V. L. Miller, and W. E. Goldman. 2007. A plasminogen-activating protease specifically controls the development of primary pneumonic plague. Science. 315(5811): 509-513.
Cathelyn, J. A., S. D. Crosby, W. W. Lathem, W. E. Goldman, and V. L. Miller. 2006. RovA, a global regulator of Yersinia pestis, specifically required for bubonic plague. Proc. Natl. Acad. Sci. USA. 103(36): 13514-13519.
Lathem, W. W., S. D. Crosby, V. L. Miller, and W. E. Goldman. 2005. Progression of primary pneumonic plague: A mouse model of infection, pathology, and bacterial transcriptional activity. Proc. Natl. Acad. Sci. USA. 102(49): 17786-17791.
