OBJECTIVE: Melioidosis is a frequent cause of severe sepsis in Southeast Asia 
caused by the gram-negative bacterium Burkholderia pseudomallei. Patients with 
melioidosis have elevated circulating levels of tissue-type plasminogen 
activator, an important regulator of fibrinolysis. In this study, we aimed to 
investigate the role of tissue-type plasminogen activator during melioidosis.
DESIGN: Animal study.
SETTING: University research laboratory.
SUBJECTS: Wild-type and tissue-type plasminogen activator-deficient C57BL/6 
mice.
INTERVENTIONS: Mice were intranasally infected with viable Burkholderia 
pseudomallei and killed after 24, 48, or 72 hrs for harvesting of lungs, liver, 
and blood. Additionally, survival studies were performed.
MEASUREMENTS AND MAIN RESULTS: Experimentally induced melioidosis was associated 
with elevated levels of tissue-type plasminogen activator in lungs of infected 
wild-type mice. During infection with Burkholderia pseudomallei, tissue-type 
plasminogen activator-deficient mice were protected when compared to wild-type 
mice as demonstrated by a strongly decreased mortality (62% vs. 100% amongst 
wild-type mice, p < .0001), together with decreased pulmonary bacterial loads, 
less severe histopathological scores, and decreased fibrinolysis. These results 
were accompanied with an early increase in cytokine levels in tissue-type 
plasminogen activator-deficient mice.
CONCLUSIONS: During severe gram-negative sepsis caused by Burkholderia 
pseudomallei, endogenous tissue-type plasminogen activator has harmful effects 
with respect to survival and pulmonary bacterial growth. These effects are 
related to tissue-type plasminogen activator-associated plasmin-induced 
fibrinolysis and/or a tissue-type plasminogen activator-associated decrease in 
proinflammatory cytokine production.