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Mice lacking the lectin-like domain of thrombomodulin are protected against melioidosis
Liesbeth M Kager1, W Joost Wiersinga, Joris J T H Roelofs
11Center 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.
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.
Insights
The thrombomodulin lectin-like domain plays a detrimental role in Gram-negative sepsis caused by Burkholderia pseudomallei. Mice lacking this domain showed improved survival and reduced inflammation during sepsis.
Area of Science:
- Immunology
- Vascular Biology
- Infectious Diseases
Background:
- Thrombomodulin (TM) is a vascular endothelial receptor with anti-inflammatory properties attributed to its lectin-like domain (TMD).
- Burkholderia pseudomallei is a Gram-negative bacterium causing melioidosis, a significant cause of sepsis in Southeast Asia and a biothreat agent.
Purpose of the Study:
- To investigate the role of the thrombomodulin lectin-like domain in the host response to Burkholderia pseudomallei sepsis.
- To determine if the TMD influences survival, bacterial clearance, and systemic inflammation during Gram-negative sepsis.
Main Methods:
- An animal study using wild-type mice and mice genetically modified to lack the thrombomodulin lectin-like domain.
- Intranasal infection with live B. pseudomallei, followed by assessment of survival, bacterial loads in organs (lungs, liver, spleen, blood), and systemic inflammation markers.
Main Results:
- Mice lacking the TMD exhibited enhanced survival rates compared to wild-type controls.
- Significantly reduced bacterial loads were observed in blood and organs of mice lacking the TMD.
- Attenuated systemic inflammation, preserved kidney and liver function, and reduced organ damage were noted in mice lacking the TMD.
Conclusions:
- The thrombomodulin lectin-like domain plays a detrimental role in the host response to Gram-negative sepsis caused by B. pseudomallei.
- Targeting the TMD may represent a therapeutic strategy to improve outcomes in sepsis patients.
