Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase- and urokinase receptor-deficient mice

We explored the role of urokinase and tissue-type plasminogen activators (u PA and tPA), as well as the uPA receptor (uPAR; CD87 in mouse severe malari a (SM), using genetically deficient (-/-) mice. The mortality resulting fro m Plasmodium berghei ANKA infection was delayed in uPA(-/-) and uPAR(-/-) m ice but was similar to that of the wild type (+/+) in tPA(-/-) mice. Parasi temia levels were similar in uPA-/-, uPAR(-/-), and +/+ mice, Production of tumor necrosis factor, as judged from the plasma level and the mRNA levels in brain and lung, was markedly increased by infection in both +/+ and uPA R(-/-) mice. Breakdown of the blood brain barrier, as evidenced by the leak age of Evans Blue, was similar in +/+ and uPAR(-/-) mice. SM was associated with a profound thrombocytopenia, which was attenuated in uPA(-/-) and uPA R(-/-) mice. Administration of aprotinin, a plasmin antagonist, also delaye d mortality and attenuated thrombocytopenia. Platelet trapping in cerebral venules or alveolar capillaries was evident in +/+ mice but absent in uPAR( -/-) mice. In contrast, macrophage sequestration in cerebral venules or alv eolar capillaries was evident in both +/+ and uPAR(-/-) mice. Polymorphonuc lear leukocyte sequestration in alveolar capillaries was similar in +/+ and uPAR(-/-) mice. These results demonstrate that the uPAR deficiency attenua tes the severity of SM, probably by its important role in platelet kinetics and trapping, These results therefore suggest that platelet sequestration contributes to the pathogenesis of SM.