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

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.