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Published on: December 9, 2022
Overexpression of activated protein C is detrimental during severe experimental gram-negative sepsis (melioidosis)
Liesbeth M Kager1, W Joost Wiersinga, Joris J T H Roelofs
11Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, Amsterdam, the Netherlands. 2Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, Amsterdam, the Netherlands. 3Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands. 4Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands. 5Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. 6Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands. 7Department of Clinical Chemistry and Pathobiochemistry, Otto-von-Guericke University, Magdeburg, Germany.
Objective:
The interplay between inflammation and blood coagulation is an essential part of host defense during severe pneumosepsis. Melioidosis, instigated by the Gram-negative bacterium Burkholderia pseudomallei, is a frequent cause of pneumosepsis in Southeast Asia. Patients with severe pneumosepsis, including melioidosis, have decreased circulating levels of protein C. Activated protein C has anticoagulant and anti-inflammatory properties. In this study, we aimed to investigate the effect of sustained elevated activated protein C levels on the host response during melioidosis.
Design:
Animal study.
Setting:
University research laboratory.
Subjects:
Wild type and activated protein C overexpressing C57BL/6 mice.
Interventions:
Mice were intranasally infected with viable B. pseudomallei and killed after 24, 48, or 72 hours for harvesting of lungs, liver, spleen, and blood. Additionally, survival studies were performed.
Measurements And Main Results:
Plasma activated protein C concentrations in activated protein C overexpressing mice (median 18.1 ng/mL) were in the same range as previously measured in patients treated with recombinant human activated protein C. Activated protein C overexpressing mice demonstrated enhanced susceptibility to B. pseudomallei infection compared with wild type mice as evidenced by a strongly increased mortality accompanied by enhanced bacterial loads in the lungs, blood, and distant organs 48 hours after infection. Additionally, at this time point, activated protein C overexpressing mice showed elevated levels of proinflammatory cytokines in lungs and plasma, together with increased pulmonary histopathology scores and neutrophil influx. At 72 hours postinfection, decreased levels of thrombin-antithrombin complexes, reflecting inhibition of coagulation, were measured in lungs of activated protein C overexpressing mice.
Conclusion:
Constitutively enhanced expression of activated protein C impairs host defense during severe Gram-negative sepsis caused by B. pseudomallei.
Insights
Sustained high levels of activated protein C (APC) worsen outcomes in melioidosis, a severe bacterial infection. Enhanced APC expression increased mortality and bacterial spread, impairing the host defense against Burkholderia pseudomallei.
Area of Science:
- Sepsis research
- Infectious disease immunology
- Coagulation and inflammation pathways
Background:
- Severe pneumosepsis, often caused by Burkholderia pseudomallei (melioidosis), involves complex interactions between inflammation and blood coagulation.
- Patients with severe pneumosepsis exhibit reduced levels of protein C, a key regulator with anticoagulant and anti-inflammatory properties.
Purpose of the Study:
- To investigate the impact of sustained elevated activated protein C (APC) levels on the host's immune response during experimental melioidosis.
Main Methods:
- An animal model using wild type and APC-overexpressing C57BL/6 mice intranasally infected with B. pseudomallei.
- Assessment of mortality, bacterial loads, cytokine levels, and pulmonary pathology at 24, 48, and 72 hours post-infection.
Main Results:
- APC-overexpressing mice showed significantly increased mortality and bacterial dissemination compared to wild-type controls.
- Elevated pro-inflammatory cytokines and neutrophil infiltration were observed in APC-overexpressing mice.
- Evidence of coagulation inhibition (decreased thrombin-antithrombin complexes) was noted in APC-overexpressing mice at later time points.
Conclusions:
- Constitutively enhanced APC expression compromises host defense mechanisms against severe Gram-negative sepsis, specifically in the context of melioidosis.
- The findings suggest a complex role for APC in sepsis, where elevated levels may be detrimental.
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