Faculty Collaboration Database

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

04/26/2014

Pubmed ID

24762740

Pubmed Central ID

PMC3998929

DOI

10.1371/journal.pntd.0002819

Scopus ID

2-s2.0-84901269512 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

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 T

Author

Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Burkholderia pseudomallei
Male
Melioidosis
Mice
Mice, Inbred C57BL
Mutant Proteins
Pneumonia, Bacterial
Point Mutation
Protein C
Sepsis
Survival Analysis
Thrombomodulin