Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram-negative sepsis (melioidosis)

Melioidosis is a frequent cause of sepsis in Southeast Asia caused by the Gram-negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of plasminogen activator inhibitor type 1 (PAI-1), an important regulator of inflammation and fibrinolysis. In this study, we aimed to investigate the role of PAI-1 during melioidosis. Wild-type (WT) and PAI-1-deficient (PAI-1-/1(-/-) ) mice were intranasally infected with B. pseudomallei. Mice were killed after 24, 48 or 72 h. Lungs, liver and blood were harvested for measurement of bacterial loads, cytokines, clinical chemistry, histopathology, and coagulation parameters. Additionally, survival studies were performed. PAI-1(-/-) mice demonstrated enhanced susceptibility to B. pseudomallei infection, as shown by a strongly increased mortality rate (100% vs. 58% among WT mice, P < 0.001), associated with enhanced bacterial loads in lungs, liver, and blood. Additionally, PAI-1(-/-) mice showed elevated levels of proinflammatory cytokines in lungs and plasma, accompanied by enhanced local and systemic coagulation activation (thrombin-antithrombin complexes and D-dimer), increased hepatocellular injury (plasma aspartate aminotransferase and alanine aminotransferase), and renal failure (plasma creatinine and urea). PAI-1 has a protective role during severe Gram-negative sepsis caused by B. pseudomallei by limiting bacterial growth, inflammation, and coagulation, and probably, as a consequence thereof, distant organ injury