Page 264 - Haematologica May 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1424-1435
Hemostasis
The contact system proteases play disparate roles in streptococcal sepsis
Juliane Köhler,1 Claudia Maletzki,2 Dirk Koczan,3 Marcus Frank,4
Carolin Trepesch,1* Alexey S. Revenko,5 Jeffrey R. Crosby,5 A. Robert Macleod,5 Stefan Mikkat6 and Sonja Oehmcke-Hecht1
1Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, Rostock, Germany; 2Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Care, Rostock University Medical Center, Rostock, Germany; 3Center for Medical Research – Core Facility Micro-Array-Technologie, Rostock
4
University Medical Center, Rostock, Germany; Medical Biology and Electron Microscopy
Centre, Rostock University Medical Center, Rostock, Germany; 5Department of Antisense Drug Discovery, Ionis Pharmaceuticals Inc., Carlsbad, CA, USA and 6Core Facility Proteome Analysis, Rostock University Medical Center, Rostock, Germany
*Current address: Department of Anesthesiology and Operative Intensive Care Medicine,
Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin; Freie Universität Berlin, Humboldt- Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
ABSTRACT
Sepsis causes an activation of the human contact system, an inflamma- tory response mechanism against foreign surfaces, proteins and pathogens. The serine proteases of the contact system, factor XII and plasma kallikrein, are decreased in plasma of septic patients, which was pre- viously associated with an unfavorable outcome. However, the precise mechanisms and roles of contact system factors in bacterial sepsis are poorly understood. We, therefore, studied the physiological relevance of factor XII and plasma kallikrein in a mouse model of experimental sepsis. We show that decreased plasma kallikrein concentration in septic mice is a result of reduced mRNA expression plasma prekallikrein gene, indicating that plasma kallikrein belong to negative acute phase proteins. Investigations regarding the pathophysiological function of contact system proteases during sepsis revealed different roles for factor XII and plasma kallikrein. In vitro, factor XII decelerated bacteria induced fibrinolysis, whereas plasma kallikrein support- ed it. Remarkably, depletion of plasma kallikrein (but not factor XII) by treat- ment with antisense-oligonucleotides, dampens bacterial dissemination and growth in multiple organs in the mouse sepsis model. These findings iden- tify plasma kallikrein as a novel host pathogenicity factor in Streptococcus pyogenes sepsis.
Introduction
Sepsis and severe sepsis are life-threatening complications caused by a dysregulat- ed host response to bacterial infection and activation of coagulation. The liver plays a key role in these events due to the acute phase protein response, an increased or decreased synthesis of host defense and coagulation proteins. Increased production of acute phase proteins contribute to a procoagulant state in sepsis, especially by enhancing production of procoagulants such as fibrinogen, and by decreasing liver synthesis of antithrombin.1 A procoagulant state is thought to be protective against bacterial dissemination, as local activation of coagulation traps bacteria in a fibrin mesh and activates inflammatory reactions.2,3 Inhibition of fibrinolysis may support this process further, since highly invasive pathogens exploit the host fibrinolytic sys- tem to degrade fibrin clots and overcome tissue barriers.2 Streptococcus pyogenes is a Gram-positive major human pathogen causing mainly local infections of the skin and mucous membranes such as erysipelas or tonsillitis. Local infections occasionally develop into serious systemic complications, of which streptococcal toxic shock syn- drome and necrotizing fasciitis are associated with high morbidity and mortality.3
Correspondence:
SONJA OEHMCKE-HECHT
sonja.oehmcke-hecht@med.uni-rostock.de
Received: April 3, 2019. Accepted: July 12, 2019. Pre-published: July 18, 2019.
doi:10.3324/haematol.2019.223545
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1424
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