Overexpression of the endothelial protein C receptor is detrimental during pneumonia-derived gram-negative sepsis (Melioidosis)

Autor: Liesbeth M. Kager, Joost C. M. Meijers, Arjen M. Dondorp, J. Daan de Boer, Lionel Lattenist, Tom van der Poll, Joris J. T. H. Roelofs, Cornelis van 't Veer, Marcel Levi, Marcel Schouten, W. Joost Wiersinga, Charles T. Esmon
Přispěvatelé: AII - Amsterdam institute for Infection and Immunity, Gastroenterology and Hepatology, Infectious diseases, Other departments, ACS - Amsterdam Cardiovascular Sciences, Pathology, Vascular Medicine, Experimental Vascular Medicine, Center of Experimental and Molecular Medicine
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Bacterial Diseases
Male
Melioidosis
Mouse
medicine.medical_treatment
Mice
Gram Negative
Receptor
Asia
Southeastern
Aged
80 and over
Mice
Knockout
Endothelial protein C receptor
biology
lcsh:Public aspects of medicine
Endothelial Protein C Receptor
Animal Models
Middle Aged
Bacterial Pathogens
Host-Pathogen Interaction
Infectious Diseases
Medicine
Female
medicine.symptom
medicine.drug
Research Article
Adult
lcsh:Arctic medicine. Tropical medicine
Asia
Adolescent
lcsh:RC955-962
Inflammation
Receptors
Cell Surface
Microbiology
Sepsis
Young Adult
Model Organisms
Antigens
CD
medicine
Pneumonia
Bacterial
Animals
Humans
Biology
Aged
Protease
Public Health
Environmental and Occupational Health
lcsh:RA1-1270
medicine.disease
biology.organism_classification
Survival Analysis
Mice
Inbred C57BL
Disease Models
Animal
Burkholderia
Immunology
Burkholderia Infection
Protein C
Zdroj: PLoS Neglected Tropical Diseases
PLoS neglected tropical diseases, 7(7). Public Library of Science
PLoS Neglected Tropical Diseases, Vol 7, Iss 7, p e2306 (2013)
ISSN: 1935-2735
1935-2727
Popis: 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.
Author Summary During pneumonia and sepsis a procoagulant state is observed, with activation of coagulation and downregulation of anticoagulant pathways, both closely interrelated with inflammation. The protein C (PC) system is an important anticoagulant pathway implicated in the pathogenesis of sepsis. The rate of conversion of the zymogen PC into the active end product of the PC system, activated PC, is enhanced when PC binds to the endothelial protein C receptor (EPCR). 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 and a serious potential bioterrorism threat agent. Plasma EPCR-levels measured in culture-proven melioidosis patients were higher than in healthy controls and were associated with an increased mortality. Furthermore, mice overexpressing EPCR 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, while endogenous EPCR does not impact on the host response. These data point to a possible role for EPCR in the host defense against B. pseudomallei and may be of value in the development of therapeutic strategies against this dangerous pathogen.
Databáze: OpenAIRE
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