The balance between coagulation and fibrinolysis is essential not only to maintain homeostasis but also to enable an appropriate response to trauma and infection. In addition, there exists an intimate link between fibrin deposition and inflammation. Some bacterial pathogens, however, have developed virulence strategies to manipulate the host thrombotic and fibrinolytic pathways. The Gram-negative bacterium Yersinia pestis causes the disease plague, which can manifest in three distinct forms: bubonic, septicemic, and pneumonic. If untreated, Y. pestis infection is associated with high levels of morbidity and mortality, particularly when the bacteria are introduced into the lungs. We have shown that the bacterial virulence factor Pla, the plasminogen activator protease, is essential for Y. pestis to cause primary pneumonic plague and is required to induce a pro-inflammatory state in the lungs. Interestingly, the role of Pla during pneumonic plague appears to be significantly different that its role during bubonic plague, and therefore the mechanisms by which Pla contributes to the virulence of the bacterium in the lungs are unknown. In vitro, Pla converts host plasminogen to the active plasmin form. Plasmin breaks down fibrin clots, enhancing fibrinolysis, which is thought to allow the bacteria to replicate and spread. In addition, Pla inactivates 12-antiplasmin, the major inhibitor of plasmin. We hypothesize that, through the activation of plasmin and degradation of 12-antiplasmin, Y. pestis uses Pla induce a highly fibrinolytic state, which in turn alters the inflammatory response to the infection, resulting in the development of a rapidly progressing and severe pneumonia. We propose to determine the extent of pulmonary thrombosis induced by Y. pestis, the roles that plasminogen and fibrinogen play in the control of pneumonic plague, the effects that Pla has on coagulation and fibrinolysis, and the contribution of these factors to the development of the pro-inflammatory state that develops in the lungs during primary pneumonic plague.

Public Health Relevance

The disease plague has caused an estimated 200 million deaths over the course of human history, and continues to be a public health threat, both worldwide and in the United States. An understanding of the mechanisms by which Yersinia pestis causes primary pneumonic plague through the alteration of coagulation and fibrinolysis is essential to developing effective countermeasures against this bacterium. This project is designed to elucidate those mechanisms at a genetic and biochemical level, and may have implications for understanding how other bacterial pathogens affect thrombosis and fibrinolysis during infection as well.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Mukhopadhyay, Suman
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
Schools of Medicine
United States
Zip Code
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
Caulfield, Adam J; Walker, Margaret E; Gielda, Lindsay M et al. (2014) The Pla protease of Yersinia pestis degrades fas ligand to manipulate host cell death and inflammation. Cell Host Microbe 15:424-34
Caulfield, Adam J; Lathem, Wyndham W (2014) Disruption of fas-fas ligand signaling, apoptosis, and innate immunity by bacterial pathogens. PLoS Pathog 10:e1004252
Eddy, Justin L; Gielda, Lindsay M; Caulfield, Adam J et al. (2014) Production of outer membrane vesicles by the plague pathogen Yersinia pestis. PLoS One 9:e107002
Lathem, Wyndham W; Schroeder, Jay A; Bellows, Lauren E et al. (2014) Posttranscriptional regulation of the Yersinia pestis cyclic AMP receptor protein Crp and impact on virulence. MBio 5:e01038-13
Houppert, Andrew S; Bohman, Lesley; Merritt, Peter M et al. (2013) RfaL is required for Yersinia pestis type III secretion and virulence. Infect Immun 81:1186-97

Showing the most recent 10 out of 12 publications