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Essentials    Effect of plasminogen activator inhibitor (PAI)‐1 on plague and its  Y. pestis  cleavage is unknown.  An intranasal mouse model of infection was used to determine the role of PAI‐1 in pneumonic plague.  PAI‐1 is cleaved and inactivated by the Pla protease of  Y. pestis  in the lung airspace.  PAI‐1 impacts both bacterial outgrowth and the immune response to respiratory  Y. pestis  infection.Click to hear Dr Bock discuss pathogen activators of plasminogen .    Summary   Background  The hemostatic regulator plasminogen activator inhibitor‐1 ( PAI ‐1) inactivates endogenous plasminogen activators and aids in the immune response to bacterial infection.  Yersinia pestis , the causative agent of plague, produces the Pla protease, a virulence factor that is required during plague. However, the specific hemostatic proteins cleaved by Pla  in vivo  that contribute to pathogenesis have not yet been fully elucidated.    Objectives  To determine whether  PAI ‐1 is cleaved by the Pla protease during pneumonic plague, and to define the impact of  PAI ‐1 on  Y. pestis  respiratory infection in the presence or absence of Pla.    Methods  An intranasal mouse model of pneumonic plague was used to assess the levels of total and active  PAI ‐1 in the lung airspace, and the impact of  PAI ‐1 deficiency on bacterial pathogenesis, the host immune response and plasmin generation following infection with wild‐type or ∆ pla Y. pestis .    Results  We found that  Y. pestis  cleaves and inactivates  PAI ‐1 in the lungs in a Pla‐dependent manner. The loss of  PAI ‐1 enhances  Y. pestis  outgrowth in the absence of Pla, and is associated with increased conversion of plasminogen to plasmin. Furthermore, we found that  PAI ‐1 regulates immune cell recruitment, cytokine production and tissue permeability during pneumonic plague.    Conclusions  Our data demonstrate that  PAI ‐1 is an  in vivo  target of the Pla protease in the lungs, and that  PAI ‐1 is a key regulator of the pulmonary innate immune response. We conclude that the inactivation of  PAI ‐1 by  Y. pestis  alters the host environment to promote virulence during pneumonic plague.

Proteolysis of plasminogen activator inhibitor‐1 by Yersinia pestis remodulates the host environment to promote virulence