A Thrombomodulin Mutation That Impairs Active Protein C Generation is Detrimental in Severe Pneumonia-derived Gram-negative Sepsis (melioidosis)

Overview

Journal PLoS Negl Trop Dis

Specialties Infectious Diseases
Tropical Medicine

Date 2014 Apr 26

PMID 24762740

Citations 5

Authors

Liesbeth M Kager

W Joost Wiersinga

Joris J T H Roelofs

Onno J de Boer

Hartmut Weiler

Cornelis van t Veer

Tom van der Poll

Affiliations

Soon will be listed here.

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.

Citing Articles

The Impact of Age and Sex on Mouse Models of Melioidosis.

Klimko C, Trevino S, Moreau A, Cuadrado M, Meyer J, Fetterer D Pathogens. 2020; 9(2).

PMID: 32054106 PMC: 7168040. DOI: 10.3390/pathogens9020113.

Histopathological and immunohistochemical characterization of Burkholderia pseudomallei lesions in an acute model of infection with BALB/c mice.

Garcia-Jimenez W, Salguero F, DElia R Int J Exp Pathol. 2018; 98(6):347-355.

PMID: 29315931 PMC: 5826972. DOI: 10.1111/iep.12258.

Identification of key genes in Gram‑positive and Gram‑negative sepsis using stochastic perturbation.

Li Z, Zhang Y, Liu Y, Liu Y, Li Y Mol Med Rep. 2017; 16(3):3133-3146.

PMID: 28714002 PMC: 5548058. DOI: 10.3892/mmr.2017.7013.

Thrombomodulin Protects Against Bacterial Keratitis, Is Anti-Inflammatory, but Not Angiogenic.

McClellan S, Ekanayaka S, Li C, Jiang X, Barrett R, Hazlett L Invest Ophthalmol Vis Sci. 2016; 56(13):8091-100.

PMID: 26720461 PMC: 5110241. DOI: 10.1167/iovs.15-18393.

Bone Marrow Mesenchymal Stem Cells Alleviate Extracellular Kynurenine Levels, as Detected by High-Performance Liquid Chromatography.

Wang Y, Zhao J, Tan L, Huang Y, Li D, Quan S Inflammation. 2015; 38(4):1450-7.

PMID: 25854176 DOI: 10.1007/s10753-015-0119-z.

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