The role of the human contact system during sepsis

• Applicant: Dr. Sonja Oehmcke-Hecht
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 316733765

The general aim of this project is to identify the function of contact factors during invasive streptococcal infection and define the relative contributions of the intrinsic and extrinsic coagulation pathway in streptococcal sepsis. The findings of this application may help to indentify novel diagnostic tools or targets for the treatment of severe infectious diseases.My previous work has shown an important role of the coagulation system for the entrapment of bacteria in a clot followed by their killing. These data support the concept that coagulation is an innate immune mechanism. The human contact system contributes to pathological thrombus formation, but the role of the contact system during immunothrombosis is not known. Depletion of contact factors is often seen in plasma of septic patients and this may lead to the formation of unstable clots. Such unstable clots may be unable to trap and kill bacteria. Unstable clots may also release microthrombi into the circulation and contribute to severe haemostatic complications, which are associated with high mortality. The project presented in this application will focus on this important clinical problem, as the importance of the contact system during invasive infections is still not completely understood. To address this task experimentally, I will - in addition to in vitro investigations - employ antisense-oligonucleotide technology, to knock-down expression of the contact system in mice. This approach will give novel insights in the role of the contact system in sepsis and delineate the relative contributions of the intrinsic and extrinsic pathway in streptococcal sepsis. Further novel information will be gained about the pathophysiological functions of contact factors inside a fibrin clot and whether individual contact factors are consumed or down-regulated during infection.

• DFG Programme: Research Grants