Overexpression of the Endothelial Protein C Receptor Is Detrimental during Pneumonia-Derived Gram-negative Sepsis (Melioidosis)

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. methodology/principal findings: 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. conclusion/significance: 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. © 2013 kager et al.