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

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 du...

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Published in:	PLoS neglected tropical diseases Vol. 7; no. 7; p. e2306
Main Authors:	Kager, Liesbeth M., Schouten, Marcel, Wiersinga, W. Joost, de Boer, J. Daan, Lattenist, Lionel C. W., Roelofs, Joris J. T. H., Meijers, Joost C. M., Levi, Marcel, Dondorp, Arjen M., Esmon, Charles T., van 't Veer, Cornelis, van der Poll, Tom
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 11.07.2013 Public Library of Science (PLoS)
Subjects:	Adolescent Adult Aged Aged, 80 and over Animals Anticoagulants Antigens, CD - blood Asia Asia, Southeastern Binding sites Biology Burkholderia Cytokines Disease Models, Animal Endothelial Protein C Receptor Experiments Female Grants Humans Male Medical research Medicine Melioidosis - pathology Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Mortality Pathogenesis Plasma Pneumonia Pneumonia, Bacterial - complications Proteins Receptors, Cell Surface - blood Rodents Sepsis Sepsis - pathology Survival Analysis Young Adult Humans Mice, Inbred C57BL Middle Aged Pneumonia, Bacterial Male Receptors, Cell Surface Mice, Knockout Asia, Southeastern Melioidosis Young Adult Aged, 80 & over Animals Asia Adolescent Survival Analysis Adult Female Sepsis Aged Mice Antigens, CD Disease Models, Animal
ISSN:	1935-2735, 1935-2727, 1935-2735
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Summary:	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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Conceived and designed the experiments: LMK WJW CvV TvdP. Performed the experiments: LMK MS JDdB LCWL JJTHR ML JCMM. Analyzed the data: LMK JJTHR JCMM CvV TvdP. Contributed reagents/materials/analysis tools: JCMM ML AMD CTE. Wrote the paper: LMK MS WJW JDdB LCWL JJTHR JCMM ML AMD CTE CvV TvdP. The authors have declared that no competing interests exist.
ISSN:	1935-2735 1935-2727 1935-2735
DOI:	10.1371/journal.pntd.0002306