• Liesbeth M Kager, W Joost Wiersinga, Joris J T H Roelofs, Onno J de Boer, Hartmut Weiler, Cornelis van 't Veer, and Tom van der Poll.
• Center for Experimental and Molecular Medicine, Academic Medical Center-University of Amsterdam, Amsterdam, The Netherlands; Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center-University of Amsterdam, Amsterdam, The Netherlands.
• PLoS Negl Trop Dis. 2014 Apr 1;8(4):e2819.

BackgroundDuring severe (pneumo)sepsis inflammatory and coagulation pathways become activated as part of the host immune response. Thrombomodulin (TM) is involved in a range of host defense mechanisms during infection and plays a pivotal role in activation of protein C (PC) into active protein C (APC). APC has both anticoagulant and anti-inflammatory properties. In this study we investigated the effects of impaired TM-mediated APC generation during melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia caused by Burkholderia (B.) pseudomallei.Methodology/Principal Findings(WT) mice and mice with an impaired capacity to activate protein C due to a point mutation in their Thbd gene (TMpro/pro mice) were intranasally infected with B. pseudomallei and sacrificed after 24, 48 or 72 hours for analyses. Additionally, survival studies were performed. When compared to WT mice, TMpro/pro mice displayed a worse survival upon infection with B. pseudomallei, accompanied by increased coagulation activation, enhanced lung neutrophil influx and bronchoalveolar inflammation at late time points, together with increased hepatocellular injury. The TMpro/pro mutation had limited if any impact on bacterial growth and dissemination.Conclusion/SignificanceTM-mediated protein C activation contributes to protective immunity after infection with B. pseudomallei. These results add to a better understanding of the regulation of the inflammatory and procoagulant response during severe Gram-negative (pneumo)sepsis.

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