Steptococcal proteins and endotoxin adsorbing dialysis - new treatment targets in septic shock

We investigate how proteins from streptococcal bacteria stimulate the immune system of man and if it is possible to help patients with severe sepsis by using a special kind of dialysis treatment.

Septic shock has mortality rates of 40-70% due to organ failure caused by an extreme response of the innate immune system. It is generally acknowledged that septic shock arises from an overwhelming response of the innate immunity system. Immune cells, e.g. macrophages, as well as cells in the blood vessel wall, have surface-bound pattern recognition receptors (PRRs), which recognize conserved bacterial molecules (PAMPs). Upon binding, an innate immune response is initiated and orchestrated by the synthesis and release of pro- and anti-inflammatory cytokines.

Blood culture identifies a Gram-positive bacterium in 30 to 50% of septic shock cases, Group A Stroptococci are most prevalent but during the last decade an increasing frequency of Streptococcus dysgalactiae subsp. Equisimilis (SDSE) has been registered.

The overall purpose of the project is to find new targets for treatment of patients with sepsis and septic shock caused by streptococci group A (GAS) and streptococci group G (GGS). We hope to achieve this by attaining, in order, the following goals:
1. Identify substances from GAS and GGS that activate cells of the innate immune system and induce vascular inflammation.
2. Identify host receptors recognizing these substances and explore signalling pathways.
3. Investigate if the substances and whole bacteria in vivo trigger systemic inflammatory response syndrome (SIRS).
4. Explore effects of PPR antagonists in clinical sepsis.
5. In Gram-negative sepsis, treatment with endotoxin adsorbing dialysis could be beneficial.

Laboratory experiments will be performed using cell lines, tissue from rats, transgenic mice and humans (obtained during operations). Clinically beneficial effects of PRR antagonists and endotoxin adsorbing dialysis will be evaluated in patients with septic shock subject to intensive care.

All previous attempts for pharmacological intervention in septic shock have been unsuccessful. Manipulation of receptor function by antagonists and/or reducing endotoxin levels by dialysis could be a means for controlling the septic reaction.