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.


RESULTS
(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.


CONCLUSIONS
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.
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.
Liesbeth M
LM
Kager
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; Division of Infectious Diseases, Academic Medical Center-University of Amsterdam, Amsterdam, The Netherlands.
W Joost
WJ
Wiersinga
Department of Pathology, Academic Medical Center-University of Amsterdam, Amsterdam, The Netherlands.
Joris J T H
JJ
Roelofs
Department of Pathology, Academic Medical Center-University of Amsterdam, Amsterdam, The Netherlands.
Onno J
OJ
de Boer
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States of America.
Hartmut
H
Weiler
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.
Cornelis
C
van 't Veer
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; Division of Infectious Diseases, Academic Medical Center-University of Amsterdam, Amsterdam, The Netherlands.
Tom
T
van der Poll
D000818:Animals; D016957:Burkholderia pseudomallei / Q000276:immunology*; D008297:Male; D008554:Melioidosis / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000235:genetics* / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000150:complications / Q000276:immunology* / Q000473:pathology; D017354:Point Mutation; D011486:Protein C / Q000276:immunology* / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000473:pathology; D016019:Survival Analysis; D018180:Thrombomodulin / Q000235:genetics / Q000276:immunology*
D050505:Mutant Proteins; D011486:Protein C; C569169:THBD protein, mouse; D018180:Thrombomodulin