A thrombomodulin mutation that impairs active protein C generation is detrimental in severe pneumonia-derived gram-negative sepsis (melioidosis). PLoS Negl Trop Dis 2014 Apr;8(4):e2819
Date
04/26/2014Pubmed ID
24762740Pubmed Central ID
PMC3998929DOI
10.1371/journal.pntd.0002819Scopus ID
2-s2.0-84901269512 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
Author List
Kager LM, Wiersinga WJ, Roelofs JJ, de Boer OJ, Weiler H, van 't Veer C, van der Poll TAuthor
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBurkholderia pseudomallei
Male
Melioidosis
Mice
Mice, Inbred C57BL
Mutant Proteins
Pneumonia, Bacterial
Point Mutation
Protein C
Sepsis
Survival Analysis
Thrombomodulin