Biographical Sketch

Dr.  Lathem earned his A.B. in Biology from Vassar College in 1996. After working for two years as a research technician in the laboratory of Dr. James E. Darnell, Jr. at the Rockefeller University in New York City, Dr. Lathem obtained a Ph.D. in Microbiology on the pathogenesis of Escherichia coli O157:H7 at the University of Wisconsin – Madison in 2003 in the laboratory of Dr. Rodney A. Welch. He subsequently undertook a post-doctoral fellowship in the Molecular Microbiology department at the Washington University School of Medicine in St. Louis in the laboratory of Dr. William E. Goldman. Dr. Virginia L. Miller served as a co-advisor to his work during this period. Dr. Lathem joined Northwestern University as an assistant professor in 2008.



Research Abstract

Few infectious diseases have had as profound an impact on the course of human civilization as the bacterium Yersinia pestis, the cause of plague. Historically, Y. pestis has been a source of significant human morbidity and mortality, being the repeated causative agent of epidemics and pandemics, and becoming known as the “black death” during the Middle Ages. More recently, Y. pestis has re-emerged as a public health concern in multiple countries, including Malawi, Mozambique, and the Democratic Republic of Congo. In addition, the potential exists for Y. pestis to be used as a weapon of bioterrorism or biowarfare, thus the bacterium is classified as a category A select agent by the U.S. government.


Y. pestis infection in humans is an acute febrile disease that can have a number of different presentations depending upon the route of inoculation; these include bubonic plague, pneumonic plague, and septicemic plague. Although a Y. pestis infection is readily treatable with antibiotics, the disease is aggressive and delays in treatment or misdiagnosis are almost universally fatal. This is especially true of primary pneumonic plague, which would be the most likely presentation of victims of a biological warfare attack that utilized Y. pestis. Unfortunately, little is known about the interaction between Y. pestis and its mammalian host, especially during a respiratory infection. Thus, the focus of my laboratory’s research is to understand and define the molecular mechanisms by which Y. pestis causes the most severe form of disease, pneumonic plague.


A key molecule that is required for the development of a severe respiratory infection by Y. pestis is the bacterial plasminogen activating protease Pla. Indeed, in a mouse model of pneumonic plague, the absence of Pla eliminates the development of a pneumonia and shifts the disease from the respiratory form to a septicemic one. Quite unexpectedly, we found that Pla has considerably different effects on the course of disease during mammalian infection depending on the route of entry and organs colonized, one of the only examples of a bacterial virulence factor to exhibit such profound differences in this manner. Thus, it appears that the mechanisms by which Y. pestis employs Pla to cause pneumonic plague are distinct from those during bubonic plague. In addition, Pla is required for Y. pestis to initiate an overwhelming and destructive pulmonary inflammatory response in the latter half of the infection, which likely contributes to the eventual death of the animal. However, the mechanisms by which Pla contributes to disease during pneumonic plague are completely unknown, including the effects of Pla on lung function, bacterial replication, and the host immune response, particularly the coagulation and fibrinolytic cascades.


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 unclear which of the six secreted proteins is required to cause pneumonic plague. Therefore, another area of study in the laboratory is centered on determining which of these proteins is 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. In the long term, I anticipate that these studies will be applicable to other systems, with the goal of identifying common themes and unique aspects among bacterial respiratory infections.


Yersinia pestis bacteria (brown) overwhelm the lungs of mice (yellow) during pneumonic plague.




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.


Schiano, C. A., L. E. Bellows, and W. W. Lathem. 2010. The small RNA chaperone Hfq is required for the virulence of Yersinia pseudotuberculosis. Infect. Immun. 78(5): 2034-2044.


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