Urokinase receptor is necessary for bacterial defense against pneumonia-derived septic melioidosis by facilitating phagocytosis.
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.
Wiersinga
W Joost
WJ
Center for Infection and Immunity Amsterdam, University of Amsterdam, Amsterdam, The Netherlands. w.j.wiersinga@amc.uva.nl
Kager
Liesbeth M
LM
Hovius
Joppe W R
JW
van der Windt
Gerritje J W
GJ
de Vos
Alex F
AF
Meijers
Joost C M
JC
Roelofs
Joris J
JJ
Dondorp
Arjen
A
Levi
Marcel
M
Day
Nicholas P
NP
Peacock
Sharon J
SJ
van der Poll
Tom
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016470:Bacteremia / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D016957:Burkholderia pseudomallei / Q000276:immunology*; D002464:Cell Migration Inhibition / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008554:Melioidosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D055293:Receptors, Urokinase Plasminogen Activator