Maintenance of vascular homeostasis is a vital physiological process that balances thrombosis with fibrinolysis through a series of carefully regulated proteolytic pathways. Central to this process is the serine protease plasmin, which is the primary enzyme responsible for breaking down fibrin clots. Plasmin is maintained in the circulation in an inactive form as the zymogen plasminogen, and the activation of plasminogen into plasmin is tightly regulated due to the wide-ranging effects of plasmin on fibrinolysis, tissue barrier integrity, cell migration, cell death pathways, and inflammatory responses. It is not surprising, then, that several bacterial pathogens have developed virulence strategies to co-opt the plasminogen system to cause disease. Among these, the bacterium Yersinia pestis is easily transmitted and results in a rapidly progressing, often fatal disease called plague. Y. pestis produces the omptin-family outer membrane protease virulence factor Pla, and we have shown that this Pla protease is absolutely required for Y. pestis to cause the severe respiratory disease known as pneumonic plague. In an effort to understand the mechanisms by which Pla contributes to the development of pneumonic plague, we recently demonstrated that Pla efficiently converts host plasminogen to plasmin in vivo within the lung airspace, and this plasminogen activating ability of Pla enables Y. pestis to proliferate in the pulmonary compartment to extremely high levels, approaching 1010 colony-forming units in the lungs by 3 days. Furthermore, we found that plasminogen is required to stimulate a massive proinflammatory response in the lungs specifically through the activation of the inflammasome component caspase-1, resulting in the development of a fulminant pneumonia, tissue damage, immune cell recruitment, and a shortened time to death. Thus, in the absence of either Pla or plasminogen, bacterial outgrowth is prevented and inflammation is halted, demonstrating that plasminogen is the key host factor through which Y. pestis causes pneumonic plague. As Y. pestis relies on host plasminogen for disease, in this application we propose 1) to determine the mechanisms by which plasmin(ogen) stimulates pulmonary inflammation via caspase-1 in a Pla-dependent manner, 2) to define the spatial and temporal effects of the Yersinia type III secretion system vs. plasmin(ogen) and Pla on pulmonary inflammation, and 3) to identify the specific mechanisms by which plasmin(ogen) enables the outgrowth of Y. pestis in the lungs. In total, these studies will allow us to comprehensively examine the mechanisms by which Y. pestis interferes with vascular homeostasis and the resulting consequences on host physiology and immunity.
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 activation of plasminogen, and the molecular links between plasminogen activation and inflammation, 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 other plasminogen-mediated diseases as well.
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|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|
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|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|
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