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Primary pneumonic plague is transmitted easily, progresses rapidly, and causes high mortality, but the mechanisms by which Yersinia pestis overwhelms the lungs are largely unknown. We show that the plasminogen activator Pla is essential for Y. pestis to cause primary pneumonic plague but is less important for dissemination during pneumonic plague than during bubonic plague. Experiments manipulating its temporal expression showed that Pla allows Y. pestis to replicate rapidly in the airways, causing a lethal fulminant pneumonia; if unexpressed, inflammation is aborted, and lung repair is activated. Inhibition of Pla expression prolonged the survival of animals with the disease, offering a therapeutic option to extend the period during which antibiotics are effective.