A Thrombomodulin Mutation that Impairs Active Protein C Generation Is Detrimental in Severe Pneumonia-Derived Gram-Negative Sepsis (Melioidosis)

Background:during 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/significance:tm-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. © 2014 kager et al.