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Urokinase receptor (urokinase-type plasminogen activator receptor [uPAR], CD87), a GPI-anchored protein, is considered to play an important role in inflammation and fibrinolysis. The Gram-negative bacterium Burkholderia pseudomallei is able to survive and replicate within leukocytes and causes melioidosis, an important cause of pneumonia-derived community-acquired sepsis in Southeast Asia. In this study, we investigated the expression and function of uPAR both in patients with septic melioidosis and in a murine model of experimental melioidosis. uPAR mRNA and surface expression was increased in patients with septic melioidosis in/on both peripheral blood monocytes and granulocytes as well as in the pulmonary compartment during experimental pneumonia-derived melioidosis in mice. uPAR-deficient mice intranasally infected with B. pseudomallei showed an enhanced growth and dissemination of B. pseudomallei when compared with wild-type mice, corresponding with increased pulmonary and hepatic inflammation. uPAR knockout mice demonstrated significantly reduced neutrophil migration toward the pulmonary compartment after inoculation with B. pseudomallei. Further in vitro experiments showed that uPAR-deficient macrophages and granulocytes display a markedly impaired phagocytosis of B. pseudomallei. Additional studies showed that uPAR deficiency did not influence hemostatic and fibrinolytic responses during severe melioidosis. These data suggest that uPAR is crucially involved in the host defense against sepsis caused by B. pseudomallei by facilitating the migration of neutrophils toward the primary site of infection and subsequently facilitating the phagocytosis of B. pseudomallei.

Original publication

DOI

10.4049/jimmunol.0901008

Type

Journal article

Journal

J Immunol

Publication Date

15/03/2010

Volume

184

Pages

3079 - 3086

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Animals, Bacteremia, Burkholderia pseudomallei, Cell Migration Inhibition, Cells, Cultured, Disease Models, Animal, Humans, Melioidosis, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Neutrophil Infiltration, Neutrophils, Phagocytosis, Pneumonia, Bacterial, Receptors, Urokinase Plasminogen Activator