{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T23:08:47Z","timestamp":1783033727533,"version":"3.54.6"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2013,7,11]],"date-time":"2013-07-11T00:00:00Z","timestamp":1373500800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"DOI":"10.1371\/journal.pntd.0002306","type":"journal-article","created":{"date-parts":[[2013,7,11]],"date-time":"2013-07-11T20:47:33Z","timestamp":1373575653000},"page":"e2306","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Overexpression of the Endothelial Protein C Receptor Is Detrimental during Pneumonia-Derived Gram-negative Sepsis (Melioidosis)"],"prefix":"10.1371","volume":"7","author":[{"given":"Liesbeth M.","family":"Kager","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Schouten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Joost","family":"Wiersinga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Daan","family":"de Boer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel C. W.","family":"Lattenist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joris J. T. H.","family":"Roelofs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost C. M.","family":"Meijers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Levi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjen M.","family":"Dondorp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles T.","family":"Esmon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelis","family":"van 't Veer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"van der Poll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2013,7,11]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"e900","DOI":"10.1371\/journal.pntd.0000900","article-title":"The epidemiology and clinical spectrum of melioidosis: 540 cases from the 20 year darwin prospective study","volume":"4","author":"BJ Currie","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1128\/CMR.18.2.383-416.2005","article-title":"Melioidosis: epidemiology, pathophysiology, and management","volume":"18","author":"AC Cheng","year":"2005","journal-title":"Clin Microbiol Rev"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nrmicro1385","article-title":"Melioidosis: insights into the pathogenicity of Burkholderia pseudomallei","volume":"4","author":"WJ Wiersinga","year":"2006","journal-title":"Nat Rev Microbiol"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1056\/NEJMra1204699","article-title":"Melioidosis","volume":"367","author":"WJ Wiersinga","year":"2012","journal-title":"N Engl J Med"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1016\/S0140-6736(03)13374-0","article-title":"Melioidosis","volume":"361","author":"NJ White","year":"2003","journal-title":"Lancet"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/490456a","article-title":"Viral research faces clampdown","volume":"490","author":"D Butler","year":"2012","journal-title":"Nature"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1097\/CCM.0b013e3181c98d21","article-title":"Inflammation and coagulation","volume":"38","author":"M Levi","year":"2010","journal-title":"Crit Care Med"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1182\/blood-2009-05-199208","article-title":"Coagulation and innate immune responses: can we view them separately?","volume":"114","author":"M Delvaeye","year":"2009","journal-title":"Blood"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1182\/blood-2006-09-003004","article-title":"The cytoprotective protein C pathway","volume":"109","author":"LO Mosnier","year":"2007","journal-title":"Blood"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"26S","DOI":"10.1378\/chest.124.3_suppl.26S","article-title":"The protein C pathway","volume":"124","author":"CT Esmon","year":"2003","journal-title":"Chest"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"10212","DOI":"10.1073\/pnas.93.19.10212","article-title":"The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex","volume":"93","author":"DJ Stearns-Kurosawa","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1097\/01.moh.0000239712.93662.35","article-title":"The endothelial protein C receptor","volume":"13","author":"CT Esmon","year":"2006","journal-title":"Curr Opin Hematol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"11849","DOI":"10.1074\/jbc.M609283200","article-title":"Endothelial cell protein C receptor acts as a cellular receptor for factor VIIa on endothelium","volume":"282","author":"S Ghosh","year":"2007","journal-title":"J Biol Chem"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"28850","DOI":"10.1074\/jbc.M604966200","article-title":"Multifunctional specificity of the protein C\/activated protein C Gla domain","volume":"281","author":"RJ Preston","year":"2006","journal-title":"J Biol Chem"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1182\/blood-2010-09-310706","article-title":"Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection","volume":"117","author":"P Sen","year":"2011","journal-title":"Blood"},{"key":"ref16","first-page":"706","article-title":"Renal and urinary levels of EPCR correlate with acute renal allograft rejection","volume":"9","author":"L Lattenist","year":"2011","journal-title":"J Thromb Haemost"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1007\/s00018-011-0825-0","article-title":"The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling","volume":"69","author":"EM Gleeson","year":"2011","journal-title":"Cell Mol Life Sci"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1172\/JCI119548","article-title":"Identification of functional endothelial protein C receptor in human plasma","volume":"100","author":"S Kurosawa","year":"1997","journal-title":"J Clin Invest"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"17491","DOI":"10.1074\/jbc.271.29.17491","article-title":"The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor","volume":"271","author":"K Fukudome","year":"1996","journal-title":"J Biol Chem"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1182\/blood.V97.6.1685","article-title":"Endothelial cell protein C receptor plays an important role in protein C activation in vivo","volume":"97","author":"FB Taylor Jr","year":"2001","journal-title":"Blood"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1182\/blood.V95.5.1680.005k33_1680_1686","article-title":"The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis","volume":"95","author":"FB Taylor Jr","year":"2000","journal-title":"Blood"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1111\/j.1538-7836.2007.02592.x","article-title":"Non-hematopoietic EPCR regulates the coagulation and inflammatory responses during endotoxemia","volume":"5","author":"X Zheng","year":"2007","journal-title":"J Thromb Haemost"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1111\/j.1538-7836.2005.01385.x","article-title":"Overexpressing endothelial cell protein C receptor alters the hemostatic balance and protects mice from endotoxin","volume":"3","author":"W Li","year":"2005","journal-title":"J Thromb Haemost"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1172\/JCI42629","article-title":"Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice","volume":"120","author":"E Kerschen","year":"2010","journal-title":"J Clin Invest"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"3958","DOI":"10.1182\/blood-2004-03-1203","article-title":"Patients with severe sepsis vary markedly in their ability to generate activated protein C","volume":"104","author":"PC Liaw","year":"2004","journal-title":"Blood"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1182\/blood.V91.2.725","article-title":"Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: lack of correlation with thrombomodulin suggests involvement of different pathological processes","volume":"91","author":"S Kurosawa","year":"1998","journal-title":"Blood"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1007\/s00134-011-2171-y","article-title":"Early rise in circulating endothelial protein C receptor correlates with poor outcome in severe sepsis","volume":"37","author":"C Guitton","year":"2011","journal-title":"Intensive Care Med"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1056\/NEJM200108093450603","article-title":"Dysfunction of endothelial protein C activation in severe meningococcal sepsis","volume":"345","author":"SN Faust","year":"2001","journal-title":"N Engl J Med"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1164\/rccm.200611-1692OC","article-title":"A comparative study of the protein C pathway in septic and nonseptic patients with organ failure","volume":"176","author":"D Borgel","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1538-7836.2007.02796.x","article-title":"Activation of coagulation with concurrent impairment of anticoagulant mechanisms correlates with a poor outcome in severe melioidosis","volume":"6","author":"WJ Wiersinga","year":"2008","journal-title":"J Thromb Haemost"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ijid.2005.06.001","article-title":"Decreased protein C, protein S, and antithrombin levels are predictive of poor outcome in Gram-negative sepsis caused by Burkholderia pseudomallei","volume":"10","author":"SP LaRosa","year":"2006","journal-title":"Int J Infect Dis"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1160\/TH11-07-0504","article-title":"Diabetes does not influence activation of coagulation, fibrinolysis or anticoagulant pathways in Gram-negative sepsis (melioidosis)","volume":"106","author":"GC Koh","year":"2011","journal-title":"Thromb Haemost"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1111\/j.1538-7836.2011.04473.x","article-title":"Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram-negative sepsis (melioidosis)","volume":"9","author":"LM Kager","year":"2011","journal-title":"J Thromb Haemost"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1097\/CCM.0b013e31824ea05e","article-title":"Endogenous tissue-type plasminogen activator impairs host defense during severe experimental gram-negative sepsis (melioidosis)","volume":"40","author":"LM Kager","year":"2012","journal-title":"Crit Care Med"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"e248","DOI":"10.1371\/journal.pmed.0040248","article-title":"Toll-like receptor 2 impairs host defense in gram-negative sepsis caused by Burkholderia pseudomallei (Melioidosis)","volume":"4","author":"WJ Wiersinga","year":"2007","journal-title":"PLoS Med"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1097\/01.CCM.0000050454.01978.3B","article-title":"2001 SCCM\/ESICM\/ACCP\/ATS\/SIS International Sepsis Definitions Conference","volume":"31","author":"MM Levy","year":"2003","journal-title":"Crit Care Med"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1182\/blood-2005-01-0406","article-title":"Extraembryonic expression of EPCR is essential for embryonic viability","volume":"106","author":"W Li","year":"2005","journal-title":"Blood"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1182\/blood.V95.5.1687.005k08_1687_1693","article-title":"Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo","volume":"95","author":"JM Gu","year":"2000","journal-title":"Blood"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1055\/s-0037-1613196","article-title":"Distribution of endothelial cell protein C\/activated protein C receptor (EPCR) during mouse embryo development","volume":"88","author":"JT Crawley","year":"2002","journal-title":"Thromb Haemost"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1086\/315155","article-title":"Elevated plasma concentrations of interferon (IFN)-gamma and the IFN-gamma-inducing cytokines interleukin (IL)-18, IL-12, and IL-15 in severe melioidosis","volume":"180","author":"FN Lauw","year":"1999","journal-title":"J Infect Dis"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1182\/blood-2003-07-2520","article-title":"A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis","volume":"103","author":"B Saposnik","year":"2004","journal-title":"Blood"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"5588","DOI":"10.1128\/MCB.8.12.5588","article-title":"Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells","volume":"8","author":"EM Conway","year":"1988","journal-title":"Mol Cell Biol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1182\/blood.V73.1.159.159","article-title":"Tumor necrosis factor leads to the internalization and degradation of thrombomodulin from the surface of bovine aortic endothelial cells in culture","volume":"73","author":"KL Moore","year":"1989","journal-title":"Blood"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"26486","DOI":"10.1016\/S0021-9258(18)47220-1","article-title":"Identification, cloning, and regulation of a novel endothelial cell protein C\/activated protein C receptor","volume":"269","author":"K Fukudome","year":"1994","journal-title":"J Biol Chem"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1042\/bj2730679","article-title":"Heterogeneous regulation of constitutive thrombomodulin or inducible tissue-factor activities on the surface of human saphenous-vein endothelial cells in culture following stimulation by interleukin-1, tumour necrosis factor, thrombin or phorbol ester","volume":"273","author":"G Archipoff","year":"1991","journal-title":"Biochem J"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"6038","DOI":"10.1074\/jbc.275.8.6038","article-title":"Metalloproteolytic release of endothelial cell protein C receptor","volume":"275","author":"J Xu","year":"2000","journal-title":"J Biol Chem"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s004080000080","article-title":"Activation of protein C pathway in the airways","volume":"180","author":"O Hataji","year":"2002","journal-title":"Lung"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1164\/rccm.200206-515OC","article-title":"Activated protein C inhibits the expression of platelet-derived growth factor in the lung","volume":"167","author":"S Shimizu","year":"2003","journal-title":"Am J Respir Crit Care Med"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"L1002","DOI":"10.1152\/ajplung.90555.2008","article-title":"Activated protein C protects against ventilator-induced pulmonary capillary leak","volume":"296","author":"JH Finigan","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1038\/nm1667","article-title":"Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis","volume":"13","author":"B Isermann","year":"2007","journal-title":"Nat Med"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"3507","DOI":"10.1073\/pnas.1222878110","article-title":"Genomic responses in mouse models poorly mimic human inflammatory diseases","volume":"110","author":"J Seok","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1086\/315271","article-title":"Prognostic value of cytokine concentrations (tumor necrosis factor-alpha, interleukin-6, and interleukin-10) and clinical parameters in severe melioidosis","volume":"181","author":"AJ Simpson","year":"2000","journal-title":"J Infect Dis"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1128\/IAI.67.7.3593-3600.1999","article-title":"Obligatory role of gamma interferon for host survival in a murine model of infection with Burkholderia pseudomallei","volume":"67","author":"P Santanirand","year":"1999","journal-title":"Infect Immun"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1182\/blood-2004-06-2456","article-title":"A cardioprotective role for the endothelial protein C receptor in lipopolysaccharide-induced endotoxemia in the mouse","volume":"105","author":"T Iwaki","year":"2005","journal-title":"Blood"}],"container-title":["PLoS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pntd.0002306","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T02:48:17Z","timestamp":1688352497000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0002306"}},"subtitle":[],"editor":[{"given":"Joseph M.","family":"Vinetz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2013,7,11]]},"references-count":54,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2013,7,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0002306","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,7,11]]}}}