title: Overexpression of the endothelial protein C receptor is detrimental during pneumonia-derived gram-negative sepsis (Melioidosis).
abstract: BACKGROUND
  The endothelial protein C receptor (EPCR) enhances anticoagulation by accelerating activation of protein C to activated protein C (APC) and mediates anti-inflammatory effects by facilitating APC-mediated signaling via protease activated receptor-1. We studied the role of EPCR in the host response during pneumonia-derived sepsis instigated by Burkholderia (B.) pseudomallei, the causative agent of melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia.
  
  
  RESULTS
  Soluble EPCR was measured in plasma of patients with septic culture-proven melioidosis and healthy controls. Experimental melioidosis was induced by intranasal inoculation of B. pseudomallei in wild-type (WT) mice and mice with either EPCR-overexpression (Tie2-EPCR) or EPCR-deficiency (EPCR(-/-)). Mice were sacrificed after 24, 48 or 72 hours. Organs and plasma were harvested to measure colony forming units, cellular influxes, cytokine levels and coagulation parameters. Plasma EPCR-levels were higher in melioidosis patients than in healthy controls and associated with an increased mortality. Tie2-EPCR mice demonstrated enhanced bacterial growth and dissemination to distant organs during experimental melioidosis, accompanied by increased lung damage, neutrophil influx and cytokine production, and attenuated coagulation activation. EPCR(-/-) mice had an unremarkable response to B. pseudomallei infection as compared to WT mice, except for a difference in coagulation activation in plasma.
  
  
  CONCLUSIONS
  Increased EPCR-levels correlate with accelerated mortality in patients with melioidosis. In mice, transgenic overexpression of EPCR aggravates outcome during Gram-negative pneumonia-derived sepsis caused by B. pseudomallei, while endogenous EPCR does not impact on the host response. These results add to a better understanding of the regulation of coagulation during severe (pneumo)sepsis.
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. l.m.kager@amc.uva.nl
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.forename: Marcel
authors.initials: M
authors.lastname: Schouten
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
authors.forename: J Daan
authors.initials: JD
authors.lastname: de Boer
authors.forename: Lionel C W
authors.initials: LC
authors.lastname: Lattenist
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000097:blood*; D001208:Asia; D001210:Asia, Southeastern; D004195:Disease Models, Animal; D000074283:Endothelial Protein C Receptor; D005260:Female; D006801:Humans; D008297:Male; D008554:Melioidosis / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018410:Pneumonia, Bacterial / Q000150:complications*; D011956:Receptors, Cell Surface / Q000097:blood*; D018805:Sepsis / Q000473:pathology*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; C080248:Procr protein, mouse; D011956:Receptors, Cell Surface