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Identification and characterization of targets for the treatment of severe infections caused by Streptococcus pyogenes

Final Report Summary - STREPSEP (Identification and characterization of targets for the treatment of severe infections caused by Streptococcus pyogenes)

Background

Severe infectious diseases, including sepsis, remain a serious clinical challenge worldwide. Although the intensive care system in Europe has considerably improved over the last 20 years, a recent European study revealed that sepsis is still a life-threatening condition and its complications are associated with high mortality rates. ICU-acquired infections cause more deaths than non-ICU-acquired and keeping in mind that more than 35 % of all intensive care patients develop a sepsis at some point during their ICU stay, severe infectious diseases must be considered as a major health threat. It has been estimated that currently more patients die from sepsis than from bowel disease or lung and breast cancer.

General goal

The present application was undertaken to investigate the molecular mechanisms that lead to lung lesions and coagulopathy in severe infectious diseases with focus on the human contact system.

Studies on the molecular mechanism of the contact system inhibitor HKH20

Systemic activation of the contact system, also known as the instrisic pathway of coagulation or the kallikrein/kinin system, during sepsis has been suggested to cause severe complications such as kinin induced vascular leakage and bleeding disorders. Once activated it is also involved in the regulation of hemostatic and inflammatory processes.

During her stay at Lund University, Sonja Oehmcke showed that that HKH20, a peptide derived from human high molecular weight kininogen (HK), down-regulates inflammatory reactions caused by Streptococcus pyogenes in a mouse model of sepsis. Activation of the contact system in the bloodstream by S. pyogenes leads to massive tissue damage in the lungs of the infected mice, which eventually results in the death of the animals. Sonja Oehmcke's results show that HKH20 inhibits activation of the contact system and protects mice with invasive S. pyogenes infection from lung damage. In combination with clindamycin treatment, the peptide also significantly prolongs the survival of infected mice. The fact that HKH20 prevents lung bleedings and tissue damage, prolonged survival time and increased overall survival, could represent a novel therapeutic principle in severe infectious diseases.

Apart from eukaryotic and prokaryotic surfaces also neutrophil extracellular traps (NETs) provide an interface that allows the binding and activation of the contact system. NETs are capable to assemble and kill various bacterial and fungal species and, they are considered as an important part of the innate immune system. As contact activation leads to the processing of HK followed by the release of antibacterial peptides and bradykinin, it was tested whether recruitment and activation of the contact system by NETs amplifies the innate immune response. Indeed Sonja Oehmcke's results show that the M1 protein from S. pyogenes, in concert with human fibrinogen - triggers polymorphonuclear neutrophils to form NETs and this leads to an activation of the contact system on NETs. Taken together the data support the notion that contact activation on NETs contribute to an more efficient clearance of entrapped bacteria.

Importance

Severe infectious diseases are associated with high morbidity and mortality. Within the last years only one new drug has been launched that can be used to treat septic patients. However, due to strong side effects this drug can only be given to a small group of patients. It should be mentioned that a dramatic and fast aggravation of the state of health is often seen in these patients. Patients that survived a sepsis, severe sepsis, or septic shock often experience serious sequelae and their quality of life has dramatically changed. Any attempt that aims to prevent the occurrence of these conditions has far-reaching consequences that not only have a scientific impact, but also an impact on social, economic, and health care issues.