Mice Lacking the Lectin-Like Domain of Thrombomodulin Are Protected Against Melioidosis

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