title: Mice lacking the lectin-like domain of thrombomodulin are protected against melioidosis.
abstract: OBJECTIVE
  Thrombomodulin is a multidomain receptor primarily expressed by vascular endothelium. The lectin-like domain of thrombomodulin has anti-inflammatory properties. In this study, we investigated the role of the thrombomodulin lectin-like domain in the host response to Gram-negative sepsis caused by Burkholderia pseudomallei, a "Tier 1" biothreat agent and the causative agent of melioidosis, a common form of community-acquired sepsis in Southeast Asia.
  
  
  METHODS
  Animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Wild-type mice and mice lacking the lectin-like domain of thrombomodulin.
  
  
  METHODS
  Mice were intranasally infected with live B. pseudomallei and killed after 24, 48, or 72 hours for harvesting of lungs, liver, spleen, and blood. Additionally, survival studies were performed.
  
  
  RESULTS
  Following exposure to B. pseudomallei, mice lacking the lectin-like domain of thrombomodulin showed a survival advantage, accompanied by decreased bacterial loads in the blood, lungs, liver, and spleen. Although lung histopathology did not differ between groups, mice lacking the lectin-like domain of thrombomodulin displayed strongly attenuated systemic inflammation, as reflected by lower plasma cytokine levels, maintenance of normal kidney and liver function, histologic evidence of reduced organ damage, and damage to the spleen.
  
  
  CONCLUSIONS
  This study reveals for the first time a detrimental role for the thrombomodulin lectin-like domain in the host response to sepsis caused by a clinically relevant Gram-negative pathogen.
authors.affiliation: 1Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 3Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 4Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 5Department of Immunopathology, Sanquin, Amsterdam, The Netherlands. 6Centre for Blood Research, Life Sciences Institute, Division of Hematology-Oncology, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Ingrid
authors.initials: I
authors.lastname: Stroo
authors.forename: Ahmed
authors.initials: A
authors.lastname: Achouiti
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D058491:Bacterial Load; D001707:Biopsy, Needle; D001992:Bronchoalveolar Lavage Fluid / Q000382:microbiology; D016957:Burkholderia pseudomallei / Q000472:pathogenicity; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D037102:Lectins / Q000378:metabolism; D008168:Lung / Q000382:microbiology / Q000473:pathology*; D008297:Male; D008554:Melioidosis / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000503:physiopathology / Q000517:prevention & control*; D011897:Random Allocation; D018709:Statistics, Nonparametric; D015996:Survival Rate; D018180:Thrombomodulin / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D037102:Lectins; D018180:Thrombomodulin