Pneumonic plague is the deadliest manifestation of disease caused by the Category A select agent bacterium Yersinia pestis. Currently, the possible combination of widespread aerosol dissemination and rapid disease progression are of increased concern for defense against bioterrorism with Y. pestis. Unfortunately, there is surprisingly little information on the cellular and molecular processes responsible for Y. pestis-triggered pathology in the lung, particularly in comparison to other forms of disease caused by the plague bacillus.
My laboratory focuses on understanding the mechanisms by which Y. pestis specifically causes primary pneumonic plague. We recently discovered that a 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. One set of projects in the lab centers 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.
Y. pestis also requires for virulence a type III secretion system to inject a set of six effector proteins directly into host cells. While it has been demonstrated that bacteria lacking the entire system are avirulent and are cleared from the lungs, it is unknown which of the six secreted proteins are required to cause pneumonic plague. Therefore, a second set of projects in the lab are designed to determine which of these proteins are necessary to cause disease during respiratory infection, at what stages during the progression of the infection these proteins are required, what host cells in the lungs are affected, and the effects of these bacterial proteins on pulmonary function.
These projects combine modern molecular, genetic, and biochemical techniques with tissue culture and animal models of infection to understand the interactions of Y. pestis with the respiratory system. 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.
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.
