Urokinase receptor is necessary for bacterial defense against Gram-negative sepsis (melioidosis) by facilitating phagoctytosis

Introduction

Urokinase receptor (uPAR, CD87), a glycosylphosphatidylinositol-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. We here investigated the expression and function of uPAR both in patients with septic melioidosis and in a murine model of experimental melioidosis.

Methods

Using a translational approach we conducted a patient study in patients with culture-confirmed sepsis caused by B. pseudomallei, in vitro experiments using wild-type (WT) and uPAR knockout (KO) cells, and mouse studies using WT and uPAR KO mice inoculated with B. pseudomallei.

Results

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 WT mice, corresponding with increased pulmonary and hepatic inflammation. uPAR KO mice demonstrated significantly reduced neutrophil migration towards 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.

Conclusion

These data suggest that uPAR is crucially involved in the host defense against sepsis caused by B. pseudomallei by facilitating the migration of neutrophils towards the primary site of infection and subsequently facilitating the phagocytosis of B. pseudomallei.