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.
Design: Animal study.
Setting: University research laboratory.
Subjects: Wild-type mice and mice lacking the lectin-like domain of thrombomodulin.
Interventions: 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.
Measurements and Main 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.
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.
This work was performed at Center for Experimental and Molecular Medicine, Center for Infection and Immunity Amsterdam, and Academic Medical Center, University of Amsterdam.
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Dr. Kager is sponsored by research grants of ZonMW (project number: 92003504) and the Stichting BeGeTu. Dr. Wiersinga is sponsored by a VENI grant of The Netherlands Organisation for Scientific Research (NWO) (grant number: 91610008) and holds a ZonMw Clinical Fellow grant. His institution received grant support from NWO (VENI grant). Dr. Roelofs is sponsored by the Dutch Kidney Foundation (grant number: C09.2287). Dr. Achouiti is supported by a grant from the Landsteiner Foundation for Blood Transfusion Research (project number LSBR 0706). Dr. Conway holds a CSL-Behring Chair and a Canada Research Chair in Endothelial Cell Biology and is supported by the Canadian Institutes for Health Research and the Natural Sciences and Engineering Council of Canada. His institution received grant support from the Canadian Institutes for Health Research, Canada Research Chairs, and Natural Sciences and Engineering Research Council. The remaining authors have disclosed that they do not have any potential conflicts of interest.
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